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Pan Q, Zhang W, Chen X, Li Y, Tu C. A study of trends in body morphology, overweight, and obesity in Chinese adults aged 40-59 years. BMC Public Health 2025; 25:833. [PMID: 40025505 PMCID: PMC11874844 DOI: 10.1186/s12889-025-21890-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Accepted: 02/10/2025] [Indexed: 03/04/2025] Open
Abstract
OBJECTIVE To reveal the changing pattern of anthropometry of middle-aged adults aged 40-59 in China from 2000-2020, and to predict the development trend in the next decade, to provide a reference basis for curbing the prevalence of overweight and obesity in them. METHODS A grey GM(1,1) prediction model was established for the cross-sectional data on anthropometric measures of 422,851 adults obtained from five series of national physical fitness surveillance in China. RESULTS 1) From 2000 to 2020, all anthropometric indicators of middle-aged people aged 40-59 years in China maintained growth, with waist circumference increasing at the highest rate, weight at the second highest rate, and height at the slowest rate; 2) Overweight and obesity rates are increasing rapidly, with an average annual increase of 0.37 percentage points and 0.30 percentage points, with a greater increase for men than for women. CONCLUSION Without stronger interventions, overweight and obesity rates among middle-aged adults are likely to continue to increase in the future, and coordinated efforts are needed to slow down the obesity epidemic and improve the physical health of middle-aged adults.
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Affiliation(s)
- Qi Pan
- School of Teacher (Physical) Education, Taizhou University, Taizhou, 318000, China
- College of Physical Education, Hangzhou Normal University, Hangzhou, 311121, China
| | - Weifeng Zhang
- Department of Physical Education, Hangzhou Youth Activity Center, Hangzhou, 310016, China
| | - Xiaolong Chen
- School of Teacher (Physical) Education, Taizhou University, Taizhou, 318000, China
- College of Physical Education, Hangzhou Normal University, Hangzhou, 311121, China
| | - Yuyu Li
- School of Teacher (Physical) Education, Taizhou University, Taizhou, 318000, China
- College of Physical Education, Hangzhou Normal University, Hangzhou, 311121, China
| | - Chunjing Tu
- School of Teacher (Physical) Education, Taizhou University, Taizhou, 318000, China.
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Hajirahimkhan A, Bartom ET, Chung CH, Guo X, Berkley K, Lee O, Chen R, Cho W, Chandrasekaran S, Clare SE, Khan SA. Reprogramming SREBP1-dependent lipogenesis and inflammation in high-risk breast with licochalcone A: a novel path to cancer prevention. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.20.595011. [PMID: 39651211 PMCID: PMC11623508 DOI: 10.1101/2024.05.20.595011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2024]
Abstract
Background Anti-estrogens have had limited impact on breast cancer (BC) prevention. Novel agents with better tolerability, and efficacy beyond estrogen receptor (ER) positive BC are needed. We studied licochalcone A (LicA) for ER-agnostic BC prevention. Methods We evaluated antiproliferative effects of LicA in seven breast cell lines and its suppression of ER+ and ER- xenograft tumors in mice. High-risk human breast tissue was treated with LicA ex vivo , followed by RNA sequencing and metabolism flux modeling. Confirmatory testing was performed in an independent specimen set and ER+/- BC cell lines using NanoString metabolic panel, proteomics, western blots, and spatiotemporally resolved cholesterol quantification in single cells. Results LicA suppressed proliferation in vitro and xenograft tumor growth in vivo . It downregulated pivotal steps in PI3K-AKT-SREBP1-dependent lipogenesis, suppressed PI3K and AKT phosphorylation, SREBP1 protein expression, and cholesterol levels in the plasma membrane inner leaflet, to the levels in normal breast cells. LicA also suppressed prostaglandin E2 synthesis and PRPS1-catalyzed de novo nucleotide biosynthesis, stalling proliferation; further evident by reduced MKI67 and BCL2 proteins. Conclusions LicA targets SREBP1, a central regulator of lipogenesis and immune response, reducing pro-tumorigenic aberrations in lipid homeostasis and inflammation. It is a promising non-endocrine candidate for BC prevention.
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Lagarde CB, Thapa K, Cullen NM, Hawes ML, Salim K, Benz MC, Dietrich SR, Burow BE, Bunnell BA, Martin EC, Collins-Burow BM, Lynch RM, Hoang VT, Burow ME, Fang JS. Obesity and leptin in breast cancer angiogenesis. Front Endocrinol (Lausanne) 2024; 15:1465727. [PMID: 39439572 PMCID: PMC11493622 DOI: 10.3389/fendo.2024.1465727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 09/04/2024] [Indexed: 10/25/2024] Open
Abstract
At the time of breast cancer diagnosis, most patients meet the diagnostic criteria to be classified as obese or overweight. This can significantly impact patient outcome: breast cancer patients with obesity (body mass index > 30) have a poorer prognosis compared to patients with a lean BMI. Obesity is associated with hyperleptinemia, and leptin is a well-established driver of metastasis in breast cancer. However, the effect of hyperleptinemia on angiogenesis in breast cancer is less well-known. Angiogenesis is an important process in breast cancer because it is essential for tumor growth beyond 1mm3 in size as well as cancer cell circulation and metastasis. This review investigates the role of leptin in regulating angiogenesis, specifically within the context of breast cancer and the associated tumor microenvironment in obese patients.
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Affiliation(s)
- Courtney B. Lagarde
- Department of Medicine, Section of Hematology and Oncology, Tulane University School of Medicine, New Orleans, LA, United States
- Tulane University Cancer Center, New Orleans, LA, United States
| | - Kapil Thapa
- Department of Cell and Molecular Biology, Tulane University School of Science and Engineering, New Orleans, LA, United States
| | - Nicole M. Cullen
- Department of Medicine, Section of Hematology and Oncology, Tulane University School of Medicine, New Orleans, LA, United States
- Tulane University Cancer Center, New Orleans, LA, United States
| | - Mackenzie L. Hawes
- Department of Medicine, Section of Hematology and Oncology, Tulane University School of Medicine, New Orleans, LA, United States
- Tulane University Cancer Center, New Orleans, LA, United States
| | - Khudeja Salim
- Department of Medicine, Section of Hematology and Oncology, Tulane University School of Medicine, New Orleans, LA, United States
- Tulane University Cancer Center, New Orleans, LA, United States
| | - Megan C. Benz
- Department of Medicine, Section of Hematology and Oncology, Tulane University School of Medicine, New Orleans, LA, United States
- Tulane University Cancer Center, New Orleans, LA, United States
| | - Sophie R. Dietrich
- Department of Medicine, Section of Hematology and Oncology, Tulane University School of Medicine, New Orleans, LA, United States
- Tulane University Cancer Center, New Orleans, LA, United States
- United States Department of Agriculture Southern Regional Research Center, New Orleans, LA, United States
| | - Brandon E. Burow
- Department of Cell and Molecular Biology, Tulane University School of Science and Engineering, New Orleans, LA, United States
| | - Bruce A. Bunnell
- Department of Microbiology, Immunology, and Genetics, University of North Texas Health Science Center, Fort Worth, TX, United States
| | - Elizabeth C. Martin
- Department of Medicine, Section of Hematology and Oncology, Tulane University School of Medicine, New Orleans, LA, United States
- Tulane University Cancer Center, New Orleans, LA, United States
| | - Bridgette M. Collins-Burow
- Department of Medicine, Section of Hematology and Oncology, Tulane University School of Medicine, New Orleans, LA, United States
- Tulane University Cancer Center, New Orleans, LA, United States
| | - Ronald M. Lynch
- Department of Physiology, College of Medicine, University of Arizona, Tucson, AZ, United States
| | - Van T. Hoang
- Department of Medicine, Section of Hematology and Oncology, Tulane University School of Medicine, New Orleans, LA, United States
- Tulane University Cancer Center, New Orleans, LA, United States
| | - Matthew E. Burow
- Department of Medicine, Section of Hematology and Oncology, Tulane University School of Medicine, New Orleans, LA, United States
- Tulane University Cancer Center, New Orleans, LA, United States
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA, United States
- Department of Surgery, Tulane University School of Medicine, New Orleans, LA, United States
| | - Jennifer S. Fang
- Department of Cell and Molecular Biology, Tulane University School of Science and Engineering, New Orleans, LA, United States
- Department of Physiology, Tulane University School of Medicine, New Orleans, LA, United States
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Yende AS, Sharma D. Obesity, dysbiosis and inflammation: interactions that modulate the efficacy of immunotherapy. Front Immunol 2024; 15:1444589. [PMID: 39253073 PMCID: PMC11381382 DOI: 10.3389/fimmu.2024.1444589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 08/06/2024] [Indexed: 09/11/2024] Open
Abstract
Recent years have seen an outstanding growth in the understanding of connections between diet-induced obesity, dysbiosis and alterations in the tumor microenvironment. Now we appreciate that gut dysbiosis can exert important effects in distant target tissues via specific microbes and metabolites. Multiple studies have examined how diet-induced obese state is associated with gut dysbiosis and how gut microbes direct various physiological processes that help maintain obese state in a bidirectional crosstalk. Another tightly linked factor is sustained low grade inflammation in tumor microenvironment that is modulated by both obese state and dysbiosis, and influences tumor growth as well as response to immunotherapy. Our review brings together these important aspects and explores their connections. In this review, we discuss how obese state modulates various components of the breast tumor microenvironment and gut microbiota to achieve sustained low-grade inflammation. We explore the crosstalk between different components of tumor microenvironment and microbes, and how they might modulate the response to immunotherapy. Discussing studies from multiple tumor types, we delve to find common microbial characteristics that may positively or negatively influence immunotherapy efficacy in breast cancer and may guide future studies.
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Affiliation(s)
- Ashutosh S Yende
- Department of Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, United States
| | - Dipali Sharma
- Department of Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, United States
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Harris MA, Savas P, Virassamy B, O'Malley MMR, Kay J, Mueller SN, Mackay LK, Salgado R, Loi S. Towards targeting the breast cancer immune microenvironment. Nat Rev Cancer 2024; 24:554-577. [PMID: 38969810 DOI: 10.1038/s41568-024-00714-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/31/2024] [Indexed: 07/07/2024]
Abstract
The tumour immune microenvironment is shaped by the crosstalk between cancer cells, immune cells, fibroblasts, endothelial cells and other stromal components. Although the immune tumour microenvironment (TME) serves as a source of therapeutic targets, it is also considered a friend or foe to tumour-directed therapies. This is readily illustrated by the importance of T cells in triple-negative breast cancer (TNBC), culminating in the advent of immune checkpoint therapy in combination with cytotoxic chemotherapy as standard of care for both early and advanced-stage TNBC, as well as recent promising signs of efficacy in a subset of hormone receptor-positive disease. In this Review, we discuss the various components of the immune TME in breast cancer and therapies that target or impact the immune TME, as well as the complexity of host physiology.
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Affiliation(s)
- Michael A Harris
- The Sir Peter MacCallum Department of Medical Oncology, University of Melbourne, Melbourne, Victoria, Australia
- Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Peter Savas
- The Sir Peter MacCallum Department of Medical Oncology, University of Melbourne, Melbourne, Victoria, Australia
- Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Balaji Virassamy
- The Sir Peter MacCallum Department of Medical Oncology, University of Melbourne, Melbourne, Victoria, Australia
- Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Megan M R O'Malley
- The Sir Peter MacCallum Department of Medical Oncology, University of Melbourne, Melbourne, Victoria, Australia
- Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Jasmine Kay
- The Sir Peter MacCallum Department of Medical Oncology, University of Melbourne, Melbourne, Victoria, Australia
- Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Scott N Mueller
- Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, Victoria, Australia
| | - Laura K Mackay
- Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, Victoria, Australia
| | - Roberto Salgado
- Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
- Department of Pathology, ZAS Ziekenhuizen, Antwerp, Belgium
| | - Sherene Loi
- The Sir Peter MacCallum Department of Medical Oncology, University of Melbourne, Melbourne, Victoria, Australia.
- Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
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Al-Ghadban S, Isern SU, Herbst KL, Bunnell BA. The Expression of Adipogenic Marker Is Significantly Increased in Estrogen-Treated Lipedema Adipocytes Differentiated from Adipose Stem Cells In Vitro. Biomedicines 2024; 12:1042. [PMID: 38791004 PMCID: PMC11117526 DOI: 10.3390/biomedicines12051042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Revised: 05/03/2024] [Accepted: 05/07/2024] [Indexed: 05/26/2024] Open
Abstract
Lipedema is a chronic, idiopathic, and painful disease characterized by an excess of adipose tissue in the extremities. The goal of this study is to characterize the gene expression of estrogen receptors (ERα and ERβ), G protein-coupled estrogen receptor (GPER), and ER-metabolizing enzymes: hydroxysteroid 17-beta dehydrogenase (HSD17B1, 7, B12), cytochrome P450 (CYP19A1), hormone-sensitive lipase (LIPE), enzyme steroid sulfatase (STS), and estrogen sulfotransferase (SULT1E1), which are markers in Body Mass Index (BMI) and age-matched non-lipedema (healthy) and lipedema ASCs and spheroids. Flow cytometry and cellular proliferation assays, RT-PCR, and Western Blot techniques were used to determine the expression of ERs and estrogen-metabolizing enzymes. In 2D monolayer culture, estrogen increased the proliferation and the expression of the mesenchymal marker, CD73, in hormone-depleted (HD) healthy ASCs compared to lipedema ASCs. The expression of ERβ was significantly increased in HD lipedema ASCs and spheroids compared to corresponding healthy cells. In contrast, ERα and GPER gene expression was significantly decreased in estrogen-treated lipedema spheroids. CYP19A1 and LIPE gene expressions were significantly increased in estrogen-treated healthy ASCs and spheroids, respectively, while estrogen upregulated the expression of PPAR-ϒ2 and ERα in estrogen-treated lipedema-differentiated adipocytes and spheroids. These results indicate that estrogen may play a role in adipose tissue dysregulation in lipedema.
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Affiliation(s)
- Sara Al-Ghadban
- Department of Microbiology, Immunology and Genetics, University of North Texas Health Science Center, Fort Worth, TX 76107, USA;
| | - Spencer U. Isern
- Department of Microbiology, Immunology and Genetics, University of North Texas Health Science Center, Fort Worth, TX 76107, USA;
| | | | - Bruce A. Bunnell
- Department of Microbiology, Immunology and Genetics, University of North Texas Health Science Center, Fort Worth, TX 76107, USA;
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Johansson H, Bellerba F, Macis D, Bertelsen BE, Guerrieri-Gonzaga A, Aristarco V, Viste K, Mellgren G, Di Cola G, Costantino J, Scalbert A, Sears DD, Gandini S, DeCensi A, Bonanni B. Effect of metformin and lifestyle intervention on adipokines and hormones in breast cancer survivors: a pooled analysis from two randomized controlled trials. Breast Cancer Res Treat 2024; 205:49-59. [PMID: 38279016 PMCID: PMC11063007 DOI: 10.1007/s10549-023-07241-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Accepted: 12/20/2023] [Indexed: 01/28/2024]
Abstract
PURPOSE We investigated the effect of metformin and lifestyle intervention on metabolic, inflammatory, and steroid biomarkers of breast cancer (BC) recurrence risk in two intervention trials among BC survivors with overweight or obesity. METHODS Baseline and follow-up serum samples collected during the two trials were analyzed and data pooled. The USA trial (Reach for Health) included postmenopausal BC survivors (n = 333) randomly assigned to 6-month metformin vs placebo and lifestyle intervention (LSI) vs control (2 × 2 factorial design). The Italian trial (MetBreCS) included BC survivors (n = 40) randomized to 12-month metformin vs placebo. Insulin resistance (HOMA-IR), adipokines, cytokines, and steroids were measured. RESULTS Metformin compared to placebo showed a favorable decrease in leptin (- 8.8 vs - 3.5 ng/mL; p < 0.01) and HOMA-IR (- 0.48 vs - 0.25; p = 0.03), and an increase in SHBG (2.80 vs 1.45 nmol/L; p < 0.01). Excluding women taking aromatase inhibitors, metformin (n = 84) compared to placebo (n = 99) decreased estradiol (- 4 vs 0 pmol/L; p < 0.01), estrone (- 8 vs 2 pmol/L; p < 0.01) and testosterone (- 0.1 vs 0 nmol/L-; p = 0.02). LSI favorably affected adiponectin (0.45 vs - 0.06 ug/mL; p < 0.01), leptin (- 10.5 vs - 4.4 ng/mL; p < 0.01), HOMA-IR (- 0.6 vs 0.2; p = 0.03), and SHBG (2.7 vs 1.1 nMol/L; p = 0.04) compared to controls. The strongest impact was observed combining metformin with LSI on adipokines, CRP, SHBG, and estrogens. CONCLUSIONS Supportive healthy lifestyle programs combined with metformin to achieve maximal risk reduction among BC cancer survivors are recommended, especially for those with obesity in menopause.
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Affiliation(s)
| | | | - Debora Macis
- IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Bjørn-Erik Bertelsen
- Hormone Laboratory, Department of Medical Biochemistry and Pharmacology, Haukeland University Hospital, Bergen, Norway
| | | | | | - Kristin Viste
- Hormone Laboratory, Department of Medical Biochemistry and Pharmacology, Haukeland University Hospital, Bergen, Norway
| | - Gunnar Mellgren
- Hormone Laboratory, Department of Medical Biochemistry and Pharmacology, Haukeland University Hospital, Bergen, Norway
- Department of Clinical Science, University of Bergen, Bergen, Norway
| | | | | | - Augustin Scalbert
- International Agency for Research on Cancer, Nutrition and Metabolism Branch, Lyon, France
| | - Dorothy D Sears
- College of Health Solutions, Arizona State University, Phoenix, AZ, USA
- Moores Cancer Center, UC San Diego, La Jolla, CA, USA
- Department of Medicine, UC San Diego, La Jolla, CA, USA
| | - Sara Gandini
- IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Andrea DeCensi
- Department of Medicine and Medical Oncology, E.O. Ospedali Galliera, Genoa, Italy
- Wolfson Institute of Population Health, Queen Mary University of London, London, UK
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Heath H, Mogol AN, Santaliz Casiano A, Zuo Q, Madak-Erdogan Z. Targeting systemic and gut microbial metabolism in ER + breast cancer. Trends Endocrinol Metab 2024; 35:321-330. [PMID: 38220576 DOI: 10.1016/j.tem.2023.12.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 12/18/2023] [Accepted: 12/20/2023] [Indexed: 01/16/2024]
Abstract
Estrogen receptor-positive (ER+) breast tumors have a better overall prognosis than ER- tumors; however, there is a sustained risk of recurrence. Mounting evidence indicates that genetic and epigenetic changes associated with resistance impact critical signaling pathways governing cell metabolism. This review delves into recent literature concerning the metabolic pathways regulated in ER+ breast tumors by the availability of nutrients and endocrine therapies and summarizes research on how changes in systemic and gut microbial metabolism can affect ER activity and responsiveness to endocrine therapy. As targeting of metabolic pathways using dietary or pharmacological approaches enters the clinic, we provide an overview of the supporting literature and suggest future directions.
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Affiliation(s)
- Hannah Heath
- Department of Food Science and Human Nutrition, University of Illinois Urbana-Champaign, Urbana, IL, USA
| | - Ayca Nazli Mogol
- Division of Nutritional Sciences, University of Illinois Urbana-Champaign, Urbana, IL, USA
| | | | - Qianying Zuo
- Department of Food Science and Human Nutrition, University of Illinois Urbana-Champaign, Urbana, IL, USA
| | - Zeynep Madak-Erdogan
- Department of Food Science and Human Nutrition, University of Illinois Urbana-Champaign, Urbana, IL, USA; Division of Nutritional Sciences, University of Illinois Urbana-Champaign, Urbana, IL, USA; Carl R. Woese Institute for Genomic Biology, University of Illinois Urbana-Champaign, Urbana, IL, USA; Cancer Center at Illinois, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA.
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9
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Johansson H, Guerrieri-Gonzaga A, Gandini S, Bertelsen BE, Macis D, Serrano D, Mellgren G, Lazzeroni M, Thomas PS, Crew KD, Kumar NB, Briata IM, Galimberti V, Viale G, Vornik LA, Aristarco V, Buttiron Webber T, Spinaci S, Brown PH, Heckman-Stoddard BM, Szabo E, Bonanni B, DeCensi A. Alternative dosing regimen of exemestane in a randomized presurgical trial: the role of obesity in biomarker modulation. NPJ Breast Cancer 2024; 10:7. [PMID: 38238336 PMCID: PMC10796398 DOI: 10.1038/s41523-024-00616-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Accepted: 01/04/2024] [Indexed: 01/22/2024] Open
Abstract
In a 3-arm presurgical trial, four-six weeks exemestane 25 mg three times/week (TIW) was non-inferior to 25 mg/day (QD) in suppressing circulating estradiol in postmenopausal women with ER-positive breast cancer. Since obesity may decrease exemestane efficacy, we analyzed changes in sex steroids, adipokines, Ki-67, and drug levels in relation to obesity. Postmenopausal women with early-stage ER-positive breast cancer were randomized to either exemestane 25 mg QD (n = 57), 25 mg TIW (n = 57), or 25 mg/week (QW, n = 62) for 4-6 weeks before breast surgery. Serum and tissue pre- and post-treatment biomarkers were stratified by body mass index (BMI)< or ≥30 kg/m2. Post-treatment median exemestane and 17-OH exemestane levels were 5-6 times higher in the QD arm compared to the TIW arm. For obese women, TIW maintained comparable reductions to QD in systemic estradiol levels, although the reduction in estrone was less with the TIW regimen. There was less suppression of SHBG with the TIW versus the QD dose schedule in obese women which should result in less systemic bioavailable estrogens. Metabolically, the effect of the TIW regimen was similar to the QD regimen for obese women in terms of leptin suppression and increase in the adiponectin-leptin ratio. Reduction in tissue Ki-67 was less for obese women on the TIW regimen than QD, although changes were similar for non-obese women. Our findings suggest that TIW exemestane should be explored further for primary cancer prevention in both normal weight and obese cohorts.
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Affiliation(s)
| | | | - Sara Gandini
- IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Bjørn-Erik Bertelsen
- Hormone Laboratory, Department of Medical Biochemistry and Pharmacology, Haukeland University Hospital, Bergen, Norway
| | - Debora Macis
- IEO, European Institute of Oncology IRCCS, Milan, Italy
| | | | - Gunnar Mellgren
- Hormone Laboratory, Department of Medical Biochemistry and Pharmacology, Haukeland University Hospital, Bergen, Norway
- Department of Clinical Science, University of Bergen, Bergen, Norway
| | | | | | | | - Nagi B Kumar
- Moffitt Cancer Center, University of South Florida, Tampa, FL, USA
| | | | | | | | - Lana A Vornik
- University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | | | | | | | - Powel H Brown
- University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | | | - Eva Szabo
- Division of Cancer Prevention, NCI Bethesda, MD, USA
| | | | - Andrea DeCensi
- E.O. Galliera Hospital, Genoa, Italy
- Wolfson Institute of Population Health, Queen Mary University of London, London, UK
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10
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Thomas NS, Scalzo RL, Wellberg EA. Diabetes mellitus in breast cancer survivors: metabolic effects of endocrine therapy. Nat Rev Endocrinol 2024; 20:16-26. [PMID: 37783846 PMCID: PMC11487546 DOI: 10.1038/s41574-023-00899-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/01/2023] [Indexed: 10/04/2023]
Abstract
Breast cancer is the most common invasive malignancy in the world, with millions of survivors living today. Type 2 diabetes mellitus (T2DM) is also a globally prevalent disease that is a widely studied risk factor for breast cancer. Most breast tumours express the oestrogen receptor and are treated with systemic therapies designed to disrupt oestrogen-dependent signalling. Since the advent of targeted endocrine therapy six decades ago, the mortality from breast cancer has steadily declined; however, during the past decade, an elevated risk of T2DM after breast cancer treatment has been reported, particularly for those who received endocrine therapy. In this Review, we highlight key events in the history of endocrine therapies, beginning with the development of tamoxifen. We also summarize the sequence of reported adverse metabolic effects, which include dyslipidaemia, hepatic steatosis and impaired glucose tolerance. We discuss the limitations of determining a causal role for breast cancer treatments in T2DM development from epidemiological data and describe informative preclinical studies that suggest complex mechanisms through which endocrine therapy might drive T2DM risk and progression. We also reinforce the life-saving benefits of endocrine therapy and highlight the need for better predictive biomarkers of T2DM risk and preventive strategies for the growing population of breast cancer survivors.
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Affiliation(s)
- Nisha S Thomas
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Stephenson Cancer Center, Oklahoma City, OK, USA
- Harold Hamm Diabetes Center, Oklahoma City, OK, USA
| | - Rebecca L Scalzo
- Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Rocky Mountain Regional VA Medical Center, Aurora, CO, USA
| | - Elizabeth A Wellberg
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
- Stephenson Cancer Center, Oklahoma City, OK, USA.
- Harold Hamm Diabetes Center, Oklahoma City, OK, USA.
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11
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Nahmias-Blank D, Maimon O, Meirovitz A, Sheva K, Peretz-Yablonski T, Elkin M. Excess body weight and postmenopausal breast cancer: Emerging molecular mechanisms and perspectives. Semin Cancer Biol 2023; 96:26-35. [PMID: 37739109 DOI: 10.1016/j.semcancer.2023.09.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 09/14/2023] [Accepted: 09/15/2023] [Indexed: 09/24/2023]
Abstract
Postmenopausal, obese women have a significantly higher risk of developing estrogen receptor-positive (ER+) breast tumors, that are resistant to therapies and are associated with higher recurrence and death rates. The global prevalence of overweight/obese women has reached alarming proportions and with postmenopausal ER+ breast carcinoma (BC) having the highest incidence among the three obesity-related cancers in females (i.e., breast, endometrial and ovarian), this is of significant concern. Elucidation of the precise molecular mechanisms underlying the pro-cancerous action of obesity in ER+BC is therefore critical for disease prevention and novel treatment initiatives. Interestingly, accumulating data has shown opposing relationships between obesity and cancer in either pre- or post-menopausal women. Excess body weight is associated with an increased risk of breast cancer in postmenopausal women and a decreased risk in pre-menopausal women. Moreover, excess adiposity during early life appears to be protective against postmenopausal breast cancer, including both ER+ and ER negative BC subtypes. Overall, estrogen-dependent mechanisms have been implicated as the main driving force in obesity-related breast tumorigenesis. In the present review we discuss the epidemiologic and mechanistic aspects of association between obesity and breast tumors after menopause, mainly in the context of hormone dependency. Molecular and cellular events underlying this association present as potential avenues for both therapeutic intervention as well as the prevention of BC-promoting processes linked to excess adiposity, which is proving to be vital in an increasingly obese global population.
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Affiliation(s)
- Daniela Nahmias-Blank
- Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Ofra Maimon
- Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Amichay Meirovitz
- Legacy Heritage Oncology Center and Dr. Larry Norton Institute, Soroka University Medical Center, Be'er Sheva 84101, Israel
| | - Kim Sheva
- Legacy Heritage Oncology Center and Dr. Larry Norton Institute, Soroka University Medical Center, Be'er Sheva 84101, Israel
| | - Tamar Peretz-Yablonski
- Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; Hebrew University Medical School, Jerusalem 91120, Israel
| | - Michael Elkin
- Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; Hebrew University Medical School, Jerusalem 91120, Israel.
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12
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Hosseinpour Z, Rezaei-Tavirani M, Akbari ME. Bioinformatic Identification of Hub Genes Related to Menopause-Obesity Paradox in Breast Cancer. Int J Endocrinol Metab 2023; 21:e140835. [PMID: 38666041 PMCID: PMC11041819 DOI: 10.5812/ijem-140835] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Revised: 09/29/2023] [Accepted: 10/08/2023] [Indexed: 04/28/2024] Open
Abstract
Background Breast cancer (BC) is one of the most common cancers in women, significantly contributing to cancer-related death in the modern world. Obesity, as a worldwide epidemic besides the menopausal status, has a paradoxical association with BC. Objectives To determine the molecular mechanisms underlying the paradoxical effects of obesity on BC, a comprehensive systems biology analysis was performed. Methods Data retrieval, data preprocessing, and differential expression analysis were conducted. Weighted correlation network analysis (WGCNA) identified the gene modules associated with clinical traits. Network analysis and hub gene identification techniques revealed key regulatory genes, and functional enrichment analysis uncovered biological pathways related to hub genes. A logistic regression model was developed to predict menopausal status based on hub genes. Additionally, gene expression analysis of two important genes was performed by qPCR. Results The study identified the hub genes and molecular pathways (the PI3K-Akt signaling pathway, proteoglycans in cancer, and lipid metabolic and atherosclerosis pathways) associated with the obesity paradox in BC based on menopausal statutes. Conclusions These results may improve our understanding of the underlying mechanisms of the effects of body mass on BC and assist in identifying biomarkers and potential therapeutic targets for treating obese postmenopausal women with BC.
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Affiliation(s)
- Zahra Hosseinpour
- Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mostafa Rezaei-Tavirani
- Proteomics Research Center, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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13
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Sankofi BM, Valencia-Rincón E, Sekhri M, Ponton-Almodovar AL, Bernard JJ, Wellberg EA. The impact of poor metabolic health on aggressive breast cancer: adipose tissue and tumor metabolism. Front Endocrinol (Lausanne) 2023; 14:1217875. [PMID: 37800138 PMCID: PMC10548218 DOI: 10.3389/fendo.2023.1217875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Accepted: 08/30/2023] [Indexed: 10/07/2023] Open
Abstract
Obesity and type 2 diabetes are chronic metabolic diseases that impact tens to hundreds of millions of adults, especially in developed countries. Each condition is associated with an elevated risk of breast cancer and with a poor prognosis after treatment. The mechanisms connecting poor metabolic health to breast cancer are numerous and include hyperinsulinemia, inflammation, excess nutrient availability, and adipose tissue dysfunction. Here, we focus on adipose tissue, highlighting important roles for both adipocytes and fibroblasts in breast cancer progression. One potentially important mediator of adipose tissue effects on breast cancer is the fibroblast growth factor receptor (FGFR) signaling network. Among the many roles of FGFR signaling, we postulate that key mechanisms driving aggressive breast cancer include epithelial-to-mesenchymal transition and cellular metabolic reprogramming. We also pose existing questions that may help better understand breast cancer biology in people with obesity, type 2 diabetes, and poor metabolic health.
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Affiliation(s)
- Barbara Mensah Sankofi
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
| | - Estefania Valencia-Rincón
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
| | - Malika Sekhri
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
| | - Adriana L. Ponton-Almodovar
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, United States
- Nicolas V. Perricone Division of Dermatology, Michigan State University, East Lansing, MI, United States
- Department of Medicine, Michigan State University, East Lansing, MI, United States
| | - Jamie J. Bernard
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, United States
- Nicolas V. Perricone Division of Dermatology, Michigan State University, East Lansing, MI, United States
- Department of Medicine, Michigan State University, East Lansing, MI, United States
| | - Elizabeth A. Wellberg
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
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14
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Hajirahimkhan A, Howell C, Bartom ET, Dong H, Lantvit DD, Xuei X, Chen SN, Pauli GF, Bolton JL, Clare SE, Khan SA, Dietz BM. Breast cancer prevention with liquiritigenin from licorice through the inhibition of aromatase and protein biosynthesis in high-risk women's breast tissue. Sci Rep 2023; 13:8734. [PMID: 37253812 PMCID: PMC10229614 DOI: 10.1038/s41598-023-34762-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 05/07/2023] [Indexed: 06/01/2023] Open
Abstract
Breast cancer risk continues to increase post menopause. Anti-estrogen therapies are available to prevent postmenopausal breast cancer in high-risk women. However, their adverse effects have reduced acceptability and overall success in cancer prevention. Natural products such as hops (Humulus lupulus) and three pharmacopeial licorice (Glycyrrhiza) species have demonstrated estrogenic and chemopreventive properties, but little is known regarding their effects on aromatase expression and activity as well as pro-proliferation pathways in human breast tissue. We show that Gycyrrhiza inflata (GI) has the highest aromatase inhibition potency among these plant extracts. Moreover, phytoestrogens such as liquiritigenin which is common in all licorice species have potent aromatase inhibitory activity, which is further supported by computational docking of their structures in the binding pocket of aromatase. In addition, GI extract and liquiritigenin suppress aromatase expression in the breast tissue of high-risk postmenopausal women. Although liquiritigenin has estrogenic effects in vitro, with preferential activity through estrogen receptor (ER)-β, it reduces estradiol-induced uterine growth in vivo. It downregulates RNA translation, protein biosynthesis, and metabolism in high-risk women's breast tissue. Finally, it reduces the rate of MCF-7 cell proliferation, with repeated dosing. Collectively, these data suggest that liquiritigenin has breast cancer prevention potential for high-risk postmenopausal women.
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Affiliation(s)
- Atieh Hajirahimkhan
- Division of Breast Surgery, Department of Surgery, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, 303 E. Superior, 4-220, Chicago, IL, 60611, USA.
| | - Caitlin Howell
- Department of Physiology and Biophysics, College of Medicine, University of Illinois Chicago, Chicago, IL, USA
| | - Elizabeth T Bartom
- Department of Biochemistry and Molecular Genetics, The Louis A. Simpson and Kimberly K. Querrey Biomedical Research Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Huali Dong
- University of Illinois Cancer Center, College of Medicine, University of Illinois Chicago, Chicago, IL, USA
| | - Daniel D Lantvit
- UIC Center for Botanical Dietary Supplements Research, Pharmacognosy Institute and Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois Chicago, Chicago, IL, USA
| | - Xiaoling Xuei
- Department of Medical and Molecular Genetics, College of Medicine, Indiana University, Indianapolis, IN, USA
| | - Shao-Nong Chen
- UIC Center for Botanical Dietary Supplements Research, Pharmacognosy Institute and Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois Chicago, Chicago, IL, USA
| | - Guido F Pauli
- UIC Center for Botanical Dietary Supplements Research, Pharmacognosy Institute and Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois Chicago, Chicago, IL, USA
| | - Judy L Bolton
- UIC Center for Botanical Dietary Supplements Research, Pharmacognosy Institute and Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois Chicago, Chicago, IL, USA
| | - Susan E Clare
- Division of Breast Surgery, Department of Surgery, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, 303 E. Superior, 4-220, Chicago, IL, 60611, USA
| | - Seema A Khan
- Division of Breast Surgery, Department of Surgery, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, 303 E. Superior, 4-220, Chicago, IL, 60611, USA
| | - Birgit M Dietz
- UIC Center for Botanical Dietary Supplements Research, Pharmacognosy Institute and Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois Chicago, Chicago, IL, USA
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15
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Savva C, Copson E, Johnson PWM, Cutress RI, Beers SA. Obesity Is Associated with Immunometabolic Changes in Adipose Tissue That May Drive Treatment Resistance in Breast Cancer: Immune-Metabolic Reprogramming and Novel Therapeutic Strategies. Cancers (Basel) 2023; 15:cancers15092440. [PMID: 37173907 PMCID: PMC10177091 DOI: 10.3390/cancers15092440] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 04/20/2023] [Accepted: 04/22/2023] [Indexed: 05/15/2023] Open
Abstract
White adipose tissue (WAT) represents an endocrinologically and immunologically active tissue whose primary role is energy storage and homeostasis. Breast WAT is involved in the secretion of hormones and proinflammatory molecules that are associated with breast cancer development and progression. The role of adiposity and systemic inflammation in immune responses and resistance to anti-cancer treatment in breast cancer (BC) patients is still not clear. Metformin has demonstrated antitumorigenic properties both in pre-clinical and clinical studies. Nevertheless, its immunomodulating properties in BC are largely unknown. This review aims to evaluate the emerging evidence on the crosstalk between adiposity and the immune-tumour microenvironment in BC, its progression and treatment resistance, and the immunometabolic role of metformin in BC. Adiposity, and by extension subclinical inflammation, are associated with metabolic dysfunction and changes in the immune-tumour microenvironment in BC. In oestrogen receptor positive (ER+) breast tumours, it is proposed that these changes are mediated via a paracrine interaction between macrophages and preadipocytes, leading to elevated aromatase expression and secretion of pro-inflammatory cytokines and adipokines in the breast tissue in patients who are obese or overweight. In HER2+ breast tumours, WAT inflammation has been shown to be associated with resistance to trastuzumab mediated via MAPK or PI3K pathways. Furthermore, adipose tissue in patients with obesity is associated with upregulation of immune checkpoints on T-cells that is partially mediated via immunomodulatory effects of leptin and has been paradoxically associated with improved responses to immunotherapy in several cancers. Metformin may play a role in the metabolic reprogramming of tumour-infiltrating immune cells that are dysregulated by systemic inflammation. In conclusion, evidence suggests that body composition and metabolic status are associated with patient outcomes. To optimise patient stratification and personalisation of treatment, prospective studies are required to evaluate the role of body composition and metabolic parameters in metabolic immune reprogramming with and without immunotherapy in patients with BC.
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Affiliation(s)
- Constantinos Savva
- Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK
- CRUK Southampton Centre, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK
| | - Ellen Copson
- CRUK Southampton Centre, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK
- Southampton Experimental Cancer Medicine Centre, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK
- NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton SO16 6YD, UK
| | - Peter W M Johnson
- CRUK Southampton Centre, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK
- Southampton Experimental Cancer Medicine Centre, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK
| | - Ramsey I Cutress
- CRUK Southampton Centre, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK
- Southampton Experimental Cancer Medicine Centre, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK
- NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton SO16 6YD, UK
| | - Stephen A Beers
- Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK
- CRUK Southampton Centre, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK
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16
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Michael P, Roversi G, Brown K, Sharifi N. Adrenal Steroids and Resistance to Hormonal Blockade of Prostate and Breast Cancer. Endocrinology 2023; 164:bqac218. [PMID: 36580423 PMCID: PMC10091490 DOI: 10.1210/endocr/bqac218] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/21/2022] [Accepted: 12/28/2022] [Indexed: 12/30/2022]
Abstract
Prostate cancer and breast cancer are sex-steroid-dependent diseases that are driven in major part by gonadal sex steroids. Testosterone (T) is converted to 5α-dihydrotestosterone, both of which stimulate the androgen receptor (AR) and prostate cancer progression. Estradiol is the major stimulus for estrogen receptor-α (ERα) and proliferation of ERα-expressing breast cancer. However, the human adrenal provides an alternative source for sex steroids. A number of different androgens are produced by the adrenals, the most abundant of which is dehydroepiandrosterone (DHEA) and DHEA sulfate. These precursor steroids are subject to metabolism by peripherally expressed enzymes that are responsible for the synthesis of potent androgens and estrogens. In the case of prostate cancer, the regulation of one of these enzymatic steps occurs at least in part by way of a germline-encoded missense in 3β-hydroxysteroid dehydrogenase-1 (3βHSD1), which regulates potent androgen biosynthesis and clinical outcomes in men with advanced prostate cancer treated with gonadal T deprivation. The sex steroids that drive prostate cancer and breast cancer require a common set of enzymes for their generation. However, the pathways diverge once 3-keto, Δ4-androgens are generated and these steroids are either turned into potent androgens by steroid-5α-reductase, or into estrogens by aromatase. Alternative steroid receptors have also emerged as disease- and treatment-resistance modifiers, including a role for AR in breast cancer and glucocorticoid receptor both in breast and prostate cancer. In this review, we integrate the commonalities of adrenal steroid physiology that regulate both prostate and breast cancer while recognizing the clear distinctions between these diseases.
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Affiliation(s)
- Patrick Michael
- Genitourinary Malignancies Research Center, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA
- Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA
| | - Gustavo Roversi
- Genitourinary Malignancies Research Center, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA
| | - Kristy Brown
- Sandra and Edward Meyer Cancer Center and Department of Medicine, Weill Cornell Medicine, New York, New York 10065, USA
| | - Nima Sharifi
- Genitourinary Malignancies Research Center, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA
- Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA
- Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA
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17
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Furth PA, Wang W, Kang K, Rooney BL, Keegan G, Muralidaran V, Zou X, Flaws JA. Esr1 but Not CYP19A1 Overexpression in Mammary Epithelial Cells during Reproductive Senescence Induces Pregnancy-Like Proliferative Mammary Disease Responsive to Anti-Hormonals. THE AMERICAN JOURNAL OF PATHOLOGY 2023; 193:84-102. [PMID: 36464512 PMCID: PMC9768685 DOI: 10.1016/j.ajpath.2022.09.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 08/22/2022] [Accepted: 09/16/2022] [Indexed: 12/04/2022]
Abstract
Molecular-level analyses of breast carcinogenesis benefit from vivo disease models. Estrogen receptor 1 (Esr1) and cytochrome P450 family 19 subfamily A member 1 (CYP19A1) overexpression targeted to mammary epithelial cells in genetically engineered mouse models induces largely similar rates of proliferative mammary disease in prereproductive senescent mice. Herein, with natural reproductive senescence, Esr1 overexpression compared with CYP19A1 overexpression resulted in significantly higher rates of preneoplasia and cancer. Before reproductive senescence, Esr1, but not CYP19A1, overexpressing mice are tamoxifen resistant. However, during reproductive senescence, Esr1 mice exhibited responsiveness. Both Esr1 and CYP19A1 are responsive to letrozole before and after reproductive senescence. Gene Set Enrichment Analyses of RNA-sequencing data sets showed that higher disease rates in Esr1 mice were accompanied by significantly higher expression of cell proliferation genes, including members of prognostic platforms for women with early-stage hormone receptor-positive disease. Tamoxifen and letrozole exposure induced down-regulation of these genes and resolved differences between the two models. Both Esr1 and CYP19A1 overexpression induced abnormal developmental patterns of pregnancy-like gene expression. This resolved with progression through reproductive senescence in CYP19A1 mice, but was more persistent in Esr1 mice, resolving only with tamoxifen and letrozole exposure. In summary, genetically engineered mouse models of Esr1 and CYP19A1 overexpression revealed a diversion of disease processes resulting from the two distinct molecular pathophysiological mammary gland-targeted intrusions into estrogen signaling during reproductive senescence.
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Affiliation(s)
- Priscilla A Furth
- Department of Oncology, Georgetown University, Washington, District of Columbia; Department of Medicine, Georgetown University, Washington, District of Columbia.
| | - Weisheng Wang
- Department of Oncology, Georgetown University, Washington, District of Columbia
| | - Keunsoo Kang
- Department of Microbiology, College of Science and Technology, Dankook University, Cheonan, Republic of Korea
| | - Brendan L Rooney
- Department of Oncology, Georgetown University, Washington, District of Columbia
| | - Grace Keegan
- Department of Oncology, Georgetown University, Washington, District of Columbia
| | - Vinona Muralidaran
- Department of Oncology, Georgetown University, Washington, District of Columbia
| | - Xiaojun Zou
- Department of Oncology, Georgetown University, Washington, District of Columbia
| | - Jodi A Flaws
- Department of Comparative Biosciences, University of Illinois Urbana-Champaign, Urbana, Illinois
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18
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Al Qteishat A, Aringazina R, Ermakov D, Demianenko E. Adipocytokine imbalance and breast cancer in obese women. J Cancer Res Ther 2023; 19:S827-S834. [PMID: 38384062 DOI: 10.4103/jcrt.jcrt_2566_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Accepted: 02/13/2023] [Indexed: 02/23/2024]
Abstract
CONTEXT Breast cancer is the most common diagnosis established in women with malignant tumors. AIMS The purpose is to investigate the blood contents of adiponectin and leptin in women with breast cancer and obesity. SETTINGS AND DESIGN A total of 140 women aged 40-50 were examined. MATERIALS AND METHODS Group 1 included 70 women from classes 1 or 2 obesity. Group 2 included 70 women with stage 1 or 2 breast cancer and classes 1 or 2 obesity. The control group included 30 apparently healthy women, with mean age of 42.5 ± 2.5 years. STATISTICAL ANALYSIS USED Statistical processing of the results obtained was performed using Statistica. RESULTS Groups 1 and 2 were statistically significantly different from each other across all parameters, except for leptin resistance. In group 2, the course of breast cancer with concomitant obesity is characterized by disrupted adipocytokine homeostasis, which manifests as a 1.94-fold decrease in the blood content of adiponectin (P < 0.05), a 4.14-fold increase in the blood content of leptin (P < 0.05), and an 8.00-fold increase in the leptin/adiponectin ratio (P < 0.05). Poorly differentiated breast tumors exhibit a more pronounced imbalance in the blood levels of adipocytokines. Thus, the serum content of leptin in women with poorly differentiated tumors (G3) was 1.79 times (P < 0.05) higher than in women with moderately differentiated tumors (G2). CONCLUSIONS The course of breast cancer with concomitant obesity is characterized by disrupted adipocytokine homeostasis and decreased adiponectin concentration in the blood.
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Affiliation(s)
- Ahmed Al Qteishat
- Department of Biological Sciences and Chemistry, University of Nizwa, Nizwa, Oman
| | - Raisa Aringazina
- Department of Internal Diseases No. 1, Non-Commercial Joint-Stock Society, West Kazakhstan Marat Ospanov Medical University, Aktobe, Kazakhstan
| | - Dmitriy Ermakov
- Department of Pharmacy, Sechenov First State Medical University, Moscow, Russian Federation
| | - Elena Demianenko
- Department of Medical Chemistry, Lugansk State Medical University, Lugansk, Ukraine
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19
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Brantley KD, Zeleznik OA, Dickerman BA, Balasubramanian R, Clish CB, Avila-Pacheco J, Rosner B, Tamimi RM, Eliassen AH. A metabolomic analysis of adiposity measures and pre- and postmenopausal breast cancer risk in the Nurses' Health Studies. Br J Cancer 2022; 127:1076-1085. [PMID: 35717425 PMCID: PMC9470549 DOI: 10.1038/s41416-022-01873-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 05/20/2022] [Accepted: 05/27/2022] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Adiposity is consistently positively associated with postmenopausal breast cancer and inversely associated with premenopausal breast cancer risk, though the reasons for this difference remain unclear. METHODS In this nested case-control study of 1649 breast cancer cases and 1649 matched controls from the Nurses' Health Study (NHS) and the NHSII, we selected lipid and polar metabolites correlated with BMI, waist circumference, weight change since age 18, or derived fat mass, and developed a metabolomic score for each measure using LASSO regression. Logistic regression was used to investigate the association between this score and breast cancer risk, adjusted for risk factors and stratified by menopausal status at blood draw and diagnosis. RESULTS Metabolite scores developed among only premenopausal or postmenopausal women were highly correlated with scores developed in all women (r = 0.93-0.96). Higher metabolomic adiposity scores were generally inversely related to breast cancer risk among premenopausal women. Among postmenopausal women, significant positive trends with risk were observed (e.g., metabolomic waist circumference score OR Q4 vs. Q1 = 1.47, 95% CI = 1.03-2.08, P-trend = 0.01). CONCLUSIONS Though the same metabolites represented adiposity in pre- and postmenopausal women, breast cancer risk associations differed suggesting that metabolic dysregulation may have a differential association with pre- vs. postmenopausal breast cancer.
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Affiliation(s)
- Kristen D Brantley
- Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA, USA.
| | - Oana A Zeleznik
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Barbra A Dickerman
- Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA, USA
| | - Raji Balasubramanian
- Department of Biostatistics and Epidemiology, University of Massachusetts Amherst, Amherst, MA, USA
| | - Clary B Clish
- Metabolomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | | | - Bernard Rosner
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
- Department of Biostatistics, Harvard TH Chan School of Public Health, Boston, MA, USA
| | - Rulla M Tamimi
- Department of Population Health Sciences, Weill Cornell Medicine, New York, NY, USA
| | - A Heather Eliassen
- Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA, USA
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
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20
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Macrophages Upregulate Estrogen Receptor Expression in the Model of Obesity-Associated Breast Carcinoma. Cells 2022; 11:cells11182844. [PMID: 36139419 PMCID: PMC9496942 DOI: 10.3390/cells11182844] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 09/08/2022] [Accepted: 09/08/2022] [Indexed: 11/17/2022] Open
Abstract
Breast cancer (BC) and obesity are two heterogeneous conditions with a tremendous impact on health. BC is the most commonly diagnosed neoplasm and the leading cause of cancer-related mortality among women, and the prevalence of obesity in women worldwide reaches pandemic proportions. Obesity is a significant risk factor for both incidence and worse prognosis in estrogen receptor positive (ER+) BC. Yet, the mechanisms underlying the association between excess adiposity and increased risk/therapy resistance/poorer outcome of ER+, but not ER−negative (ER−), BC are not fully understood. Tumor-promoting action of obesity, predominantly in ER + BC patients, is often attributed to the augmented production of estrogen in ‘obese’ adipose tissue. However, in addition to the estrogen production, expression levels of ER represent a key determinant in hormone-driven breast tumorigenesis and therapy response. Here, utilizing in vitro and in vivo models of BC, we show that macrophages, whose adverse activation by obesogenic substances is fueled by heparanase (extracellular matrix-degrading enzyme), are capable of upregulating ER expression in tumor cells, in the setting of obesity-associated BC. These findings underscore a previously unknown mechanism through which interplay between cellular/extracellular elements of obesity-associated BC microenvironment influences estrogen sensitivity—a critical component in hormone-related cancer progression and resistance to therapy.
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21
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Flanagan MR, Doody DR, Voutsinas J, Wu Q, Banda K, Sharifi N, Li CI, Gadi VK. Association of HSD3B1 Genotype and Clinical Outcomes in Postmenopausal Estrogen-Receptor-Positive Breast Cancer. Ann Surg Oncol 2022; 29:7194-7201. [PMID: 35776258 DOI: 10.1245/s10434-022-12088-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 05/30/2022] [Indexed: 12/21/2022]
Abstract
BACKGROUND Homozygous inheritance of a single-nucleotide polymorphism (1245A > C) in HSD3B1 results in an adrenal permissive phenotype of increased adrenal steroid precursor conversion to potent androgens. This is associated with poor outcomes in prostate cancer. We hypothesized that inheritance of the HSD3B1 adrenal permissive genotype would similarly negatively impact breast cancer outcomes. PATIENTS AND METHODS Germline HSD3B1 was sequenced in 644 postmenopausal women diagnosed between 2004 and 2015 with stage I-III estrogen receptor-positive (ER+), HER2/neu-negative (HER2-) breast cancer enrolled in a population-based study in western Washington. Primary endpoint was distant metastatic recurrence according to genotype. Secondary endpoint was breast cancer-specific survival. Hazard ratios (HR) were calculated using cause-specific Cox regression accounting for competing risks. RESULTS Adrenal restrictive genotype (homozygous wild type) was most prevalent (47%), followed by heterozygous (44%) and adrenal permissive (9%). There were no significant differences comparing demographic, tumor, or treatment characteristics apart from higher frequency of adrenal permissive genotype among non-Hispanic white participants (p = 0.04). After accounting for competing risks, the cumulative incidence of distant metastatic recurrence (15 events) was significantly higher among participants with adrenal permissive compared with the adrenal restrictive genotype (HR 4.9, 95% CI 1.32-18.4, p = 0.02). The adrenal permissive genotype was also predictive of breast cancer-specific mortality (HR 3.5, 95% CI 1.27-9.59, p = 0.02). CONCLUSIONS Inheritance of the HSD3B1 adrenal permissive genotype is associated with increased incidence of distant metastasis and higher cause-specific mortality in postmenopausal ER+/HER2- breast cancer. Further research is necessary to understand the effect of excess adrenal androgen metabolism in promoting breast cancer growth and progression.
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Affiliation(s)
- Meghan R Flanagan
- Breast Section, Department of Surgery, University of Washington, Seattle, WA, USA. .,Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.
| | - David R Doody
- Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - Jenna Voutsinas
- Clinical Biostatistics, Fred Hutchinson Cancer Center, Seattle, WA, USA.,Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - Qian Wu
- Clinical Biostatistics, Fred Hutchinson Cancer Center, Seattle, WA, USA.,Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - Kalyan Banda
- Division of Medical Oncology, University of Washington, Seattle, WA, USA.,Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - Nima Sharifi
- Department of Hematology and Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA.,Department of Cancer Biology, GU Malignancies Research Center, Cleveland Clinic Lerner Research Institute, Cleveland, OH, USA
| | - Christopher I Li
- Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - Vijayakrishna K Gadi
- Department of Hematology and Oncology, University of Illinois Chicago, Chicago, IL, USA.,Translational Oncology Program, University of Illinois Cancer Center, Chicago, IL, USA
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22
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Sinha A, Bavishi A, Hibler EA, Yang EH, Parashar S, Okwuosa T, DeCara JM, Brown SA, Guha A, Sadler D, Khan SS, Shah SJ, Yancy CW, Akhter N. Interconnected Clinical and Social Risk Factors in Breast Cancer and Heart Failure. Front Cardiovasc Med 2022; 9:847975. [PMID: 35669467 PMCID: PMC9163546 DOI: 10.3389/fcvm.2022.847975] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Accepted: 04/13/2022] [Indexed: 11/29/2022] Open
Abstract
Breast cancer and heart failure share several known clinical cardiovascular risk factors, including age, obesity, glucose dysregulation, cholesterol dysregulation, hypertension, atrial fibrillation and inflammation. However, to fully comprehend the complex interplay between risk of breast cancer and heart failure, factors attributed to both biological and social determinants of health must be explored in risk-assessment. There are several social factors that impede implementation of prevention strategies and treatment for breast cancer and heart failure prevention, including socioeconomic status, neighborhood disadvantage, food insecurity, access to healthcare, and social isolation. A comprehensive approach to prevention of both breast cancer and heart failure must include assessment for both traditional clinical risk factors and social determinants of health in patients to address root causes of lifestyle and modifiable risk factors. In this review, we examine clinical and social determinants of health in breast cancer and heart failure that are necessary to consider in the design and implementation of effective prevention strategies that altogether reduce the risk of both chronic diseases.
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Affiliation(s)
- Arjun Sinha
- Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Avni Bavishi
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Elizabeth A. Hibler
- Department of Preventive Medicine, Division of Cancer Epidemiology and Prevention, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Eric H. Yang
- UCLA Cardio-Oncology Program, Division of Cardiology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Susmita Parashar
- Division of Cardiology, Department of Medicine, Emory University, Atlanta, GA, United States
| | - Tochukwu Okwuosa
- Division of Cardiology, Department of Medicine, Rush University Medical Center, Chicago, IL, United States
| | - Jeanne M. DeCara
- Section of Cardiology, Department of Medicine, University of Chicago Medicine, Chicago, IL, United States
| | - Sherry-Ann Brown
- Division of Cardiology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, United States
| | - Avirup Guha
- Cardio-Oncology Program, Division of Cardiology, Medical College of Georgia at Augusta University, Augusta, GA, United States
- Cardio-Oncology Program, Division of Cardiology, The Ohio State University Medical Center, Columbus, OH, United States
| | - Diego Sadler
- Robert and Suzanne Tomsich Department of Cardiovascular Medicine, Heart, Vascular and Thoracic Institute, Cleveland Clinic Florida, Weston, FL, United States
| | - Sadiya S. Khan
- Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Sanjiv J. Shah
- Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Clyde W. Yancy
- Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Nausheen Akhter
- Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
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23
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Oghazian MB, Shirzad N, Ahadi M, Eivazi Adli S, Mollazadeh S, Radfar M. Aspirin versus placebo on estrogen levels in postmenopausal women: a double-blind randomized controlled clinical trial. BMC Pharmacol Toxicol 2022; 23:31. [PMID: 35581629 PMCID: PMC9116012 DOI: 10.1186/s40360-022-00571-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 05/13/2022] [Indexed: 11/18/2022] Open
Abstract
Background Estrogen is involved in the pathogenesis of breast and gynecological cancers. Regular use of aspirin reduces estrogen levels. The present study aimed to evaluate the effect of aspirin on estrogen levels in postmenopausal women. Methods This double-blind, placebo-controlled parallel-group trial was conducted on postmenopausal women referred to an outpatient clinic at a women’s hospital in Tehran. Volunteers were randomly assigned to receive aspirin 100 mg/day or placebo for 6 weeks. Estradiol, sex hormone-binding globulin (SHBG), and testosterone levels at baseline and at the end of the intervention were measured by ELISA. Data were analyzed using SPSS 20, Kolmogorov–Smirnov test, independent samples t-test, and Mann–Whitney U test. Results Twenty-seven and 28 participants were finally analyzed in the aspirin and placebo groups, respectively. There was no significant difference between the two groups in body mass index (BMI), age, or menopausal years. There was a statistically significant difference (p = 0.002) in the amount of change in estradiol levels of the intervention group (median=− 3.5 pg/ml) compared to the control group (median=1.5 pg/ml). In contrast, there were no significant differences between the two groups regarding testosterone and SHBG levels (p = 0.58, p = 0.32). Conclusions Since low doses of aspirin may decrease estradiol levels, it could be considered a promising adjunctive therapeutic candidate in postmenopausal women to decrease BC incidence. However, further studies with larger sample sizes, measurements of estrogen levels and its related compounds in different time points accompanied by long-term follow-ups are needed to better elucidate the potential mechanisms by which nonsteroidal anti-inflammatory drugs (NSAIDs) negatively affect breast cancer. Trial registration IRCT201012195397N1. Date of first registration: 03/01/2011.
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Affiliation(s)
- Mohammad Bagher Oghazian
- Department of Internal Medicine, Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Nooshin Shirzad
- Endocrinology and Metabolism Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahdi Ahadi
- Department of Clinical Pharmacy, School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Shalaleh Eivazi Adli
- School of Pharmacy and Pharmaceutical Sciences, Islamic Azad University of Tehran Medical Sciences, Tehran, Iran
| | - Samaneh Mollazadeh
- Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Mania Radfar
- Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
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24
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Tan K, Naylor MJ. The Influence of Modifiable Factors on Breast and Prostate Cancer Risk and Disease Progression. Front Physiol 2022; 13:840826. [PMID: 35330933 PMCID: PMC8940211 DOI: 10.3389/fphys.2022.840826] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Accepted: 02/11/2022] [Indexed: 12/31/2022] Open
Abstract
Breast and prostate cancers are among the most commonly diagnosed cancers worldwide, and together represented almost 20% of all new cancer diagnoses in 2020. For both cancers, the primary treatment options are surgical resection and sex hormone deprivation therapy, highlighting the initial dependence of these malignancies on the activity of both endogenous and exogenous hormones. Cancer cell phenotype and patient prognosis is not only determined by the collection of specific gene mutations, but through the interaction and influence of a wide range of different local and systemic components. While genetic risk factors that contribute to the development of these cancers are well understood, increasing epidemiological evidence link modifiable lifestyle factors such as physical exercise, diet and weight management, to drivers of disease progression such as inflammation, transcriptional activity, and altered biochemical signaling pathways. As a result of this significant impact, it is estimated that up to 50% of cancer cases in developed countries could be prevented with changes to lifestyle and environmental factors. While epidemiological studies of modifiable risk factors and research of the biological mechanisms exist mostly independently, this review will discuss how advances in our understanding of the metabolic, protein and transcriptional pathways altered by modifiable lifestyle factors impact cancer cell physiology to influence breast and prostate cancer risk and prognosis.
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Affiliation(s)
| | - Matthew J. Naylor
- Charles Perkins Centre, School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
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25
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Barzin M, Aryannezhad S, Bagheri M, Mahdavi M, Valizadeh M, Azizi F, Hosseinpanah F. The association of the age, period, and birth cohort with 15-year changes in body mass index and waist circumference in adults: Tehran lipid and glucose study (TLGS). BMC Public Health 2022; 22:418. [PMID: 35232416 PMCID: PMC8889713 DOI: 10.1186/s12889-022-12810-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Accepted: 02/21/2022] [Indexed: 11/12/2022] Open
Abstract
Objective To examine the association of age, period, and birth cohort with body mass index (BMI) and waist circumference (WC) changes among the participants of the Tehran Lipid and Glucose Study from 1999 to 2015. Methods This prospective cohort study included 4895 participants aged ≥20 years (41.3% men), who were divided into twelve gender stratified groups, having a ten-year age difference between them. Analyses were conducted to explicitly assess the association of age vs. period on BMI and WC changes. In addition, we evaluated BMI and WC changes among different birth cohorts. Results Upon 15 years of follow-up, the mean BMI of men and women increased from 26.0 ± 3.9 to 27.5 ± 4.3 kg/m2 and from 27.5 ± 4.8 to 29.9 ± 5.4 kg/m2 (P trend < 0.001), and this trend was accompanied by an increase in WC from 88.8 ± 10.9 to 97.8 ± 10.4 cm and from 87.3 ± 12.4 to 95.8 ± 12.1 cm, respectively (P trend < 0.001). Men and women in all age cohorts tended to have a rise in their BMI and WC with aging throughout the follow-up period. For men, this trend was more prominent in younger birth cohorts at phase III for BMI and at phases III and V for WC (indicating a significant negative association with birth cohort). For women, this trend was more prominent in older birth cohorts at both phases III and V for BMI and WC (indicating a significant positive association with the birth cohort). Conclusion The rise in BMI and WC was strongly associated with age in both sexes. The men born in the recent birth cohorts and the women born in earlier birth cohorts had the most alarming BMI and WC trends. More efforts must be spent on obesity prevention policies, especially for younger men. Supplementary Information The online version contains supplementary material available at 10.1186/s12889-022-12810-z.
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Affiliation(s)
- Maryam Barzin
- Obesity Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shayan Aryannezhad
- Obesity Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Bagheri
- Obesity Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Mahdavi
- Obesity Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Majid Valizadeh
- Obesity Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fereidoun Azizi
- Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Farhad Hosseinpanah
- Obesity Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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26
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Macêdo APA, Gonçalves MDS, Barreto Medeiros JM, David JM, Villarreal CF, Macambira SG, Soares MBP, Couto RD. Potential therapeutic effects of green tea on obese lipid profile - a systematic review. Nutr Health 2022; 28:401-415. [PMID: 35014893 DOI: 10.1177/02601060211073236] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background: Green tea, obtained from the plant Camellis sinensis, is one of the oldest drinks in the world and contains numerous bioactive compounds. Studies have demonstrated the efficacy of green tea in preventing obesity and cardiovascular diseases that may be related to the reduction of lipid levels. Aim: This study aimed to evidence, through a systematic review, the therapeutic potential of green tea on the lipid profile in preclinical studies in obese animals and clinical studies in obese individuals. Methods: This systematic review follows the recommendations of the preferred report items for systematic reviews and meta-analyses. The electronic databases, PubMed (Medline), Science Direct, Scopus, and Web of Science were consulted. Articles from January 2009 to December 2019 were selected. Results: This search resulted in twenty-nine articles were included cirtically reviewed. In experimental studies, green tea administration has been shown to reduce total cholesterol, triglycerides and low-density lipoprotein cholesterol in animals exposed to obesity-inducing diet. In humans' studies green tea was not shown to be effective for obese lipid control. Because supplementation with green tea extract reduced total cholesterol, triglycerides, low-density lipoprotein for three months at a specific dose. Conclusion: Therefore, green tea appears to act as a protective agent for dyslipidemia in obesity-induced animals. In human studies, green tea has not been shown to be effective in controlling obese lipids.
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Affiliation(s)
- Ana Paula Azevêdo Macêdo
- Postgraduate Program in Food Sciences, Faculty of Pharmacy, 28111Federal University of Bahia, Salvador, Bahia, Brazil
| | - Mariane Dos Santos Gonçalves
- Postgraduate Program in Food Sciences, Faculty of Pharmacy, 28111Federal University of Bahia, Salvador, Bahia, Brazil
| | | | - Jorge Mauricio David
- Department of Organic Chemistry, Institute of Chemistry, Federal University of Bahia, Salvador, Bahia, Brazil
| | | | - Simone Garcia Macambira
- Department of Biochemistry and Biophysics, Institute of Health Sciences, Federal University of Bahia, Salvador, Bahia, Brazil
| | - Milena Botelho Pereira Soares
- Laboratory of Tissue Engineering and Immuno Pharmacology, 42509Research Center Gonçalo Moniz, Oswaldo Cruz Foundation, Salvador, Bahia, Brazil
| | - Ricardo David Couto
- Department of Clinical and Toxicological Analysis, Faculty of Pharmacy, Federal University of Bahia, Salvador, Bahia, Brazil
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27
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Lizcano F. Roles of estrogens, estrogen-like compounds, and endocrine disruptors in adipocytes. Front Endocrinol (Lausanne) 2022; 13:921504. [PMID: 36213285 PMCID: PMC9533025 DOI: 10.3389/fendo.2022.921504] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Accepted: 09/05/2022] [Indexed: 11/13/2022] Open
Abstract
Women are subject to constitutional changes after menopause, which increases conditions and diseases prone to cardiovascular risks such as obesity and diabetes mellitus. Both estrogens and androgens influence the individual's metabolic mechanism, which controls the fat distribution and the hypothalamic organization of the regulatory centers of hunger and satiety. While androgens tend to accumulate fat in the splanchnic and the visceral region with an increase in cardiovascular risk, estrogens generate more subcutaneous and extremity distribution of adipose tissue. The absence of estrogen during menopause seems to be the main factor that gives rise to the greater predisposition of women to suffer cardiovascular alterations. However, the mechanisms by which estrogens regulate the energy condition of people are not recognized. Estrogens have several mechanisms of action, which mainly include the modification of specific receptors that belong to the steroid receptor superfamily. The alpha estrogen receptors (ERα) and the beta receptors (ERβ) have a fundamental role in the metabolic control of the individual, with a very characteristic corporal distribution that exerts an influence on the metabolism of lipids and glucose. Despite the significant amount of knowledge in this field, many of the regulatory mechanisms exerted by estrogens and ER continue to be clarified. This review will discuss the role of estrogens and their receptors on the central regulation of caloric expenditure and the influence they exert on the differentiation and function of adipocytes. Furthermore, chemical substances with a hormonal activity that cause endocrine disruption with affectation on estrogen receptors will be considered. Finally, the different medical therapies for the vasomotor manifestations of menopause and their role in reducing obesity, diabetes, and cardiovascular risk will be analyzed.
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28
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Jafari N, Kolla M, Meshulam T, Shafran JS, Qiu Y, Casey AN, Pompa IR, Ennis CS, Mazzeo CS, Rabhi N, Farmer SR, Denis GV. Adipocyte-derived exosomes may promote breast cancer progression in type 2 diabetes. Sci Signal 2021; 14:eabj2807. [PMID: 34813359 PMCID: PMC8765301 DOI: 10.1126/scisignal.abj2807] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Obesity and metabolic diseases, such as insulin resistance and type 2 diabetes (T2D), are associated with metastatic breast cancer in postmenopausal women. Here, we investigated the critical cellular and molecular factors behind this link. We found that primary human adipocytes shed extracellular vesicles, specifically exosomes, that induced the expression of genes associated with epithelial-to-mesenchymal transition (EMT) and cancer stem–like cell (CSC) traits in cocultured breast cancer cell lines. Transcription of these genes was further increased in cells exposed to exosomes shed from T2D patient–derived adipocytes or insulin-resistant adipocytes and required the epigenetic reader proteins BRD2 and BRD4 in recipient cells. The thrombospondin family protein TSP5, which is associated with cancer, was more abundant in exosomes from T2D or insulin-resistant adipocytes and partially contributed to EMT in recipient cells. Bioinformatic analysis of breast cancer patient tissue showed that greater coexpression of COMP (which encodes TSP5) and BRD2 or BRD3 correlated with poorer prognosis, specifically decreased distant metastasis–free survival. Our findings reveal a mechanism of exosome-mediated cross-talk between metabolically abnormal adipocytes and breast cancer cells that may promote tumor aggressiveness in patients with T2D.
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Affiliation(s)
- Naser Jafari
- Boston University-Boston Medical Center Cancer Center, Boston University School of Medicine, Boston, MA 02118, USA
| | - Manohar Kolla
- Boston University-Boston Medical Center Cancer Center, Boston University School of Medicine, Boston, MA 02118, USA
| | - Tova Meshulam
- Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA
| | - Jordan S. Shafran
- Boston University-Boston Medical Center Cancer Center, Boston University School of Medicine, Boston, MA 02118, USA
- Current affiliation: Abbott Laboratories, Abbott Park, IL 60064, USA
| | - Yuhan Qiu
- Boston University-Boston Medical Center Cancer Center, Boston University School of Medicine, Boston, MA 02118, USA
| | - Allison N. Casey
- Boston University-Boston Medical Center Cancer Center, Boston University School of Medicine, Boston, MA 02118, USA
- Current affiliation: University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
| | - Isabella R. Pompa
- Boston University-Boston Medical Center Cancer Center, Boston University School of Medicine, Boston, MA 02118, USA
| | - Christina S. Ennis
- Boston University-Boston Medical Center Cancer Center, Boston University School of Medicine, Boston, MA 02118, USA
| | - Carla S. Mazzeo
- Section of Gastroenterology, Boston University School of Medicine, Boston, MA 02118, USA
| | - Nabil Rabhi
- Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA
| | - Stephen R. Farmer
- Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA
| | - Gerald V. Denis
- Boston University-Boston Medical Center Cancer Center, Boston University School of Medicine, Boston, MA 02118, USA
- Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA
- Shipley Prostate Cancer Research Professor, Boston University School of Medicine, Boston, MA 02118, USA
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29
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Kruse ML, Patel M, McManus J, Chung YM, Li X, Wei W, Bazeley PS, Nakamura F, Hardaway A, Downs E, Chandarlapaty S, Thomas M, Moore HC, Budd GT, Tang WHW, Hazen SL, Bernstein A, Nik-Zainal S, Abraham J, Sharifi N. Adrenal-permissive HSD3B1 genetic inheritance and risk of estrogen-driven postmenopausal breast cancer. JCI Insight 2021; 6:e150403. [PMID: 34520399 PMCID: PMC8564898 DOI: 10.1172/jci.insight.150403] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 09/09/2021] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Genetics of estrogen synthesis and breast cancer risk has been elusive. The 1245A→C missense-encoding polymorphism in HSD3B1, which is common in White populations, is functionally adrenal permissive and increases synthesis of the aromatase substrate androstenedione. We hypothesized that homozygous inheritance of the adrenal-permissive HSD3B1(1245C) is associated with postmenopausal estrogen receptor–positive (ER-positive) breast cancer. METHODS A prospective study of postmenopausal ER-driven breast cancer was done for determination of HSD3B1 and circulating steroids. Validation was performed in 2 other cohorts. Adrenal-permissive genotype frequency was compared between postmenopausal ER-positive breast cancer, the general population, and postmenopausal ER-negative breast cancer. RESULTS Prospective and validation studies had 157 and 538 patients, respectively, for the primary analysis of genotype frequency by ER status in White female breast cancer patients who were postmenopausal at diagnosis. The adrenal-permissive genotype frequency in postmenopausal White women with estrogen-driven breast cancer in the prospective cohort was 17.5% (21/120) compared with 5.4% (2/37) for ER-negative breast cancer (P = 0.108) and 9.6% (429/4451) in the general population (P = 0.0077). Adrenal-permissive genotype frequency for estrogen-driven postmenopausal breast cancer was validated using Cambridge and The Cancer Genome Atlas data sets: 14.4% (56/389) compared with 6.0% (9/149) for ER-negative breast cancer (P = 0.007) and the general population (P = 0.005). Circulating androstenedione concentration was higher with the adrenal-permissive genotype (P = 0.03). CONCLUSION Adrenal-permissive genotype is associated with estrogen-driven postmenopausal breast cancer. These findings link genetic inheritance of endogenous estrogen exposure to estrogen-driven breast cancer. FUNDING National Cancer Institute, NIH (R01CA236780, R01CA172382, and P30-CA008748); and Prostate Cancer Foundation Challenge Award.
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Affiliation(s)
- Megan L Kruse
- Department of Hematology and Oncology, Taussig Cancer Institute
| | - Mona Patel
- GU Malignancies Research Center, Department of Cancer Biology, Lerner Research Institute
| | - Jeffrey McManus
- GU Malignancies Research Center, Department of Cancer Biology, Lerner Research Institute
| | - Yoon-Mi Chung
- GU Malignancies Research Center, Department of Cancer Biology, Lerner Research Institute
| | - Xiuxiu Li
- GU Malignancies Research Center, Department of Cancer Biology, Lerner Research Institute
| | - Wei Wei
- Cancer Biostatistics Section, Taussig Cancer Institute
| | - Peter S Bazeley
- Department of Quantitative Health Sciences, Lerner Research Institute; and
| | - Fumihiko Nakamura
- GU Malignancies Research Center, Department of Cancer Biology, Lerner Research Institute
| | - Aimalie Hardaway
- GU Malignancies Research Center, Department of Cancer Biology, Lerner Research Institute
| | - Erinn Downs
- Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Sarat Chandarlapaty
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Mathew Thomas
- Department of Hematology and Oncology, Taussig Cancer Institute
| | - Halle Cf Moore
- Department of Hematology and Oncology, Taussig Cancer Institute
| | - George T Budd
- Department of Hematology and Oncology, Taussig Cancer Institute
| | - W H Wilson Tang
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, and Heart, Vascular and Thoracic Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Stanley L Hazen
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, and Heart, Vascular and Thoracic Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Aaron Bernstein
- Academic Department of Medical Genetics, School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Serena Nik-Zainal
- Academic Department of Medical Genetics, School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Jame Abraham
- Department of Hematology and Oncology, Taussig Cancer Institute
| | - Nima Sharifi
- Department of Hematology and Oncology, Taussig Cancer Institute.,GU Malignancies Research Center, Department of Cancer Biology, Lerner Research Institute
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30
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Yousefzadeh N, Jeddi S, Shokri M, Afzali H, Norouzirad R, Kashfi K, Ghasemi A. Long Term Sodium Nitrate Administration Positively Impacts Metabolic and Obesity Indices in Ovariectomized Rats. Arch Med Res 2021; 53:147-156. [PMID: 34696904 DOI: 10.1016/j.arcmed.2021.09.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 09/07/2021] [Accepted: 09/30/2021] [Indexed: 11/02/2022]
Abstract
BACKGROUND In postmenopausal women, nitric oxide (NO) deficiency is associated with obesity and type 2 diabetes (T2D). This study aims at determining the long-term effects of low-dose nitrate administration on metabolic and obesity indices in ovariectomized (OVX) rats. METHODS OVX rat model was induced using the two dorsolateral skin incision method. Two months after ovariectomy, rats were divided into three groups (n = 10/group): Control, OVX, and OVX+nitrate, and the latter received sodium nitrate at a dose of 100 mg/L in their drinking water for nine months. Fasting serum glucose and lipid profile were measured every month. A glucose tolerance test was performed at months 1, 3, and 9 (the end of the study). Obesity indices were calculated, and histological analyses were performed on the gonadal adipose tissues at month 9. RESULTS OVX rats had impaired fasting glucose, glucose intolerance, and dyslipidemia with higher obesity indices at month 9. Nitrate improved glucose and lipid metabolism in OVX rats and decreased body weight (6.9%), body mass index (12.5%), Lee index (5.4%), adiposity index (23.9%), abdominal circumference (10.5%), and thoracic circumference (17.1%). Also, nitrate decreased adipocyte area by 49% and increased adipocyte density by 193% in gonadal adipose tissue. CONCLUSION Long-term low-dose nitrate administration improves glucose and lipid metabolism in OVX rats in association with decreasing OVX-induced adiposity, increasing adipocyte density, and decreasing adipocyte area. These findings provide support for a potential therapeutic role of nitrate in postmenopausal women with some features of metabolic syndrome.
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Affiliation(s)
- Nasibeh Yousefzadeh
- Endocrine Physiology Research Center, Research institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sajad Jeddi
- Endocrine Physiology Research Center, Research institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Majid Shokri
- Endocrine Physiology Research Center, Research institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamideh Afzali
- Endocrine Physiology Research Center, Research institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Reza Norouzirad
- School of Allied Medical Sciences, Dezful University of Medical Sciences, Dezful, Iran
| | - Khosrow Kashfi
- Department of Molecular, Cellular and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, NY, USA
| | - Asghar Ghasemi
- Endocrine Physiology Research Center, Research institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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31
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Danforth DN. The Role of Chronic Inflammation in the Development of Breast Cancer. Cancers (Basel) 2021; 13:3918. [PMID: 34359821 PMCID: PMC8345713 DOI: 10.3390/cancers13153918] [Citation(s) in RCA: 77] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 07/20/2021] [Accepted: 07/27/2021] [Indexed: 12/13/2022] Open
Abstract
Chronic inflammation contributes to the malignant transformation of several malignancies and is an important component of breast cancer. The role of chronic inflammation in the initiation and development of breast cancer from normal breast tissue, however, is unclear and needs to be clarified. A review of the literature was conducted to define the chronic inflammatory processes in normal breast tissue at risk for breast cancer and in breast cancer, including the role of lymphocyte and macrophage infiltrates, chronic active adipocytes and fibroblasts, and processes that may promote chronic inflammation including the microbiome and factors related to genomic abnormalities and cellular injury. The findings indicate that in healthy normal breast tissue there is systemic evidence to suggest inflammatory changes are present and associated with breast cancer risk, and adipocytes and crown-like structures in normal breast tissue may be associated with chronic inflammatory changes. The microbiome, genomic abnormalities, and cellular changes are present in healthy normal breast tissue, with the potential to elicit inflammatory changes, while infiltrating lymphocytes are uncommon in these tissues. Chronic inflammatory changes occur prominently in breast cancer tissues, with important contributions from tumor-infiltrating lymphocytes and tumor-associated macrophages, cancer-associated adipocytes and crown-like structures, and cancer-associated fibroblasts, while the microbiome and DNA damage may serve to promote inflammatory events. Together, these findings suggest that chronic inflammation may play a role in influencing the initiation, development and conduct of breast cancer, although several chronic inflammatory processes in breast tissue may occur later in breast carcinogenesis.
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Affiliation(s)
- David N Danforth
- Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
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Martínez-Chacón G, Yatkin E, Polari L, Deniz Dinç D, Peuhu E, Hartiala P, Saarinen N, Mäkelä S. CC chemokine ligand 2 (CCL2) stimulates aromatase gene expression in mammary adipose tissue. FASEB J 2021; 35:e21536. [PMID: 33913559 DOI: 10.1096/fj.201902485rrr] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 02/10/2021] [Accepted: 03/03/2021] [Indexed: 12/13/2022]
Abstract
Obesity is a risk factor for postmenopausal breast cancer. Obesity-related inflammation upregulates aromatase expression, the rate-limiting enzyme for estrogen synthesis, in breast adipose tissue (BAT), increasing estrogen production and cancer risk. The regulation of aromatase gene (CYP19A1) in BAT is complex, and the mechanisms linking obesity and aromatase dysregulation are not fully understood. An obesity-associated factor that could regulate aromatase is the CC chemokine ligand (CCL) 2, a pro-inflammatory factor that also activates signaling pathways implicated in CYP19A1 transcription. By using human primary breast adipose stromal cells (ASCs) and aromatase reporter (hARO-Luc) mouse mammary adipose explants, we demonstrated that CCL2 enhances the glucocorticoid-mediated CYP19A1 transcription. The potential mechanism involves the activation of PI.4 via ERK1/2 pathway. We also showed that CCL2 contributes to the pro-inflammatory milieu and aromatase expression in obesity, evidenced by increased expression of CCL2 and CYP19A1 in mammary tissues from obese hARO-Luc mice, and subcutaneous adipose tissue from obese women. In summary, our results indicate that postmenopausal obesity may promote CCL2 production in BAT, leading to exacerbation of the menopause-related inflammatory state and further stimulation of local aromatase and estrogens. These results provide new insights into the regulation of aromatase and may aid in finding approaches to prevent breast cancer.
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Affiliation(s)
- Gabriela Martínez-Chacón
- Functional Foods Forum, University of Turku, Turku, Finland.,Institute of Biomedicine, University of Turku, Turku, Finland
| | - Emrah Yatkin
- Functional Foods Forum, University of Turku, Turku, Finland.,Institute of Biomedicine, University of Turku, Turku, Finland.,Central Animal Laboratory, University of Turku, Turku, Finland
| | - Lauri Polari
- Functional Foods Forum, University of Turku, Turku, Finland.,Institute of Biomedicine, University of Turku, Turku, Finland.,Faculty of Science and Engineering, Cell Biology, Åbo Akademi University, Turku, Finland
| | - Defne Deniz Dinç
- Institute of Biomedicine, University of Turku, Turku, Finland.,FICAN West Cancer Research Laboratory, University of Turku and Turku University Hospital, Turku, Finland.,Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
| | - Emilia Peuhu
- Institute of Biomedicine, University of Turku, Turku, Finland.,FICAN West Cancer Research Laboratory, University of Turku and Turku University Hospital, Turku, Finland.,Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
| | - Pauliina Hartiala
- Institute of Biomedicine, University of Turku, Turku, Finland.,Department of Plastic and General Surgery, Turku University Hospital (TYS), Turku, Finland
| | - Niina Saarinen
- Functional Foods Forum, University of Turku, Turku, Finland.,Institute of Biomedicine, University of Turku, Turku, Finland.,Turku Center for Disease Modeling, University of Turku, Turku, Finland
| | - Sari Mäkelä
- Functional Foods Forum, University of Turku, Turku, Finland.,Institute of Biomedicine, University of Turku, Turku, Finland.,Turku Center for Disease Modeling, University of Turku, Turku, Finland
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Desharnais L, Walsh LA, Quail DF. Exploiting the obesity-associated immune microenvironment for cancer therapeutics. Pharmacol Ther 2021; 229:107923. [PMID: 34171329 DOI: 10.1016/j.pharmthera.2021.107923] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 05/11/2021] [Accepted: 06/10/2021] [Indexed: 12/12/2022]
Abstract
Obesity causes chronic low-grade inflammation and leads to changes in the immune landscape of multiple organ systems. Given the link between chronic inflammatory conditions and cancer, it is not surprising that obesity is associated with increased risk and worse outcomes in many malignancies. Paradoxically, recent epidemiological studies have shown that high BMI is associated with increased efficacy of immune checkpoint inhibitors (ICI), and a causal relationship has been demonstrated in the preclinical setting. It has been proposed that obesity-associated immune dysregulation underlies this observation by inadvertently creating a favourable microenvironment for increased ICI efficacy. The recent success of ICIs in obese cancer patients raises the possibility that additional immune-targeted therapies may hold therapeutic value in this context. Here we review how obesity affects the immunological composition of the tumor microenvironment in ways that can be exploited for cancer immunotherapies. We discuss existing literature supporting a beneficial role for obesity during ICI therapy in cancer patients, potential opportunities for targeting the innate immune system to mitigate chronic inflammatory processes, and how to pinpoint obese patients who are most likely to benefit from immune interventions without relying solely on body mass index. Given that the incidence of obesity is expanding on an international scale, we propose that understanding obesity-associated inflammation is necessary to reduce cancer mortalities and capitalize on novel therapeutic opportunities in the era of cancer immunotherapy.
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Affiliation(s)
- Lysanne Desharnais
- Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada; Department of Human Genetics, McGill University, Montreal, QC, Canada
| | - Logan A Walsh
- Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada; Department of Human Genetics, McGill University, Montreal, QC, Canada.
| | - Daniela F Quail
- Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada; Department of Physiology, Faculty of Medicine, McGill University, Montreal, QC, Canada; Department of Medicine, Division of Experimental Medicine, McGill University, Montreal, QC, Canada.
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34
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Abstract
This Review focuses on the mechanistic evidence for a link between obesity, dysregulated cellular metabolism and breast cancer. Strong evidence now links obesity with the development of 13 different types of cancer, including oestrogen receptor-positive breast cancer in postmenopausal women. A number of local and systemic changes are hypothesized to support this relationship, including increased circulating levels of insulin and glucose as well as adipose tissue-derived oestrogens, adipokines and inflammatory mediators. Metabolic pathways of energy production and utilization are dysregulated in tumour cells and this dysregulation is a newly accepted hallmark of cancer. Dysregulated metabolism is also hypothesized to be a feature of non-neoplastic cells in the tumour microenvironment. Obesity-associated factors regulate metabolic pathways in both breast cancer cells and cells in the breast microenvironment, which provides a molecular link between obesity and breast cancer. Consequently, interventions that target these pathways might provide a benefit in postmenopausal women and individuals with obesity, a population at high risk of breast cancer.
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Affiliation(s)
- Kristy A Brown
- Sandra and Edward Meyer Cancer Center and Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
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35
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Goupille C, Ouldamer L, Pinault M, Guimares C, Arbion F, Jourdan ML, Frank PG. Identification of a Positive Association between Mammary Adipose Cholesterol Content and Indicators of Breast Cancer Aggressiveness in a French Population. J Nutr 2021; 151:1119-1127. [PMID: 33831951 DOI: 10.1093/jn/nxaa432] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 08/26/2020] [Accepted: 12/10/2020] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Several studies have recently highlighted important roles for adipose tissue in cancer. However, few have examined adipose tissue cholesterol, and no study has been performed in breast adipose tissue associated with breast tumors. OBJECTIVES The present work was designed to determine if breast adipose tissue cholesterol from the tumor-surrounding area is associated with breast cancer aggressiveness. METHODS Between 2009 and 2011, 215 breast adipose tissue samples were collected at the Tours University Hospital (France) during surgery of women (aged 28-89 y) with invasive breast cancer. Associations of free cholesterol (FC), esterified cholesterol (EC), and total cholesterol (TC) amounts with clinical variables (age, BMI, and treated or untreated hypercholesterolemia) and tumor aggressiveness parameters [phenotype, grade, presence of inflammatory breast cancer (IBC), and multifocality] were tested using Student's t test and after ANOVA. RESULTS The predominant form of cholesterol in adipose tissue was FC, and 50% of patients had no detectable EC. The adipose tissue FC content (μg/mg total lipid) was 18% greater in patients >70 y old than in those 40-49 y old (P < 0.05) and the TC content tended to be 12% greater in untreated hypercholesterolemic patients than in normocholesterolemic patients (P = 0.06). Breast adipose cholesterol concentrations were increased in tissues obtained from patients with human-epidermal-growth-factor-receptor-2 (HER2) phenotype (+13% FC; P < 0.05 compared with luminal A), IBC (+15% FC; P = 0.06 compared with noninflammatory tumors), as well as with multifocal triple-negative tumors (+34% FC, P < 0.05; +30% TC, P < 0.05, compared with unifocal triple-negative tumors). Among patients with triple-negative tumors, hypercholesterolemia was significantly more common (P < 0.05) in patients with multifocal tumors (64%) than in patients with unifocal tumors (25%). CONCLUSIONS This study is the first of this magnitude that analyzes cholesterol concentrations in adipose tissue from female breast cancer patients. An increase in breast adipose tissue cholesterol content may contribute to breast cancer aggressiveness (HER2 phenotype, multifocality of triple-negative tumors, and IBC).
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Affiliation(s)
- Caroline Goupille
- CHRU de Tours, Hôpital Bretonneau, Service de Gynécologie, Tours, France.,Laboratoire "Nutrition, Growth and Cancer", Université de Tours, INSERM UMR1069, Tours, France
| | - Lobna Ouldamer
- CHRU de Tours, Hôpital Bretonneau, Service de Gynécologie, Tours, France.,Laboratoire "Nutrition, Growth and Cancer", Université de Tours, INSERM UMR1069, Tours, France
| | - Michelle Pinault
- Laboratoire "Nutrition, Growth and Cancer", Université de Tours, INSERM UMR1069, Tours, France
| | - Cyrille Guimares
- Laboratoire "Nutrition, Growth and Cancer", Université de Tours, INSERM UMR1069, Tours, France
| | - Flavie Arbion
- CHRU de Tours, Hôpital Bretonneau, Service de Pathologie, Tours, France
| | - Marie L Jourdan
- CHRU de Tours, Hôpital Bretonneau, Service de Gynécologie, Tours, France.,Laboratoire "Nutrition, Growth and Cancer", Université de Tours, INSERM UMR1069, Tours, France
| | - Philippe G Frank
- Laboratoire "Nutrition, Growth and Cancer", Université de Tours, INSERM UMR1069, Tours, France.,French Network for Nutrition and Cancer Research (NACRe network), France.,SGS France Life Services, Saint Benoît, France
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36
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Maliniak ML, Miller-Kleinhenz J, Cronin-Fenton DP, Lash TL, Gogineni K, Janssen EAM, McCullough LE. Crown-Like Structures in Breast Adipose Tissue: Early Evidence and Current Issues in Breast Cancer. Cancers (Basel) 2021; 13:2222. [PMID: 34066392 PMCID: PMC8124644 DOI: 10.3390/cancers13092222] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 04/24/2021] [Accepted: 04/26/2021] [Indexed: 12/29/2022] Open
Abstract
Obesity is an established risk factor for postmenopausal breast cancer and has been linked to worse breast cancer prognosis, most clearly for hormone receptor-positive breast cancers. The underlying mechanisms of the obesity-breast cancer association are not fully understood, but growing evidence points to the breast adipose tissue microenvironment playing an important role. Obesity-induced adipose tissue dysfunction can result in a chronic state of low-grade inflammation. Crown-like structures of the breast (CLS-B) were recently identified as a histologic marker of local inflammation. In this review, we evaluate the early evidence of CLS-B in breast cancer. Data from preclinical and clinical studies show that these inflammatory lesions within the breast are associated with local NF-κB activation, increased aromatase activity, and elevation of pro-inflammatory mediators (TNFα, IL-1β, IL-6, and COX-2-derived PGE2)-factors involved in multiple pathways of breast cancer development and progression. There is also substantial evidence from epidemiologic studies that CLS-B are associated with greater adiposity among breast cancer patients. However, there is insufficient evidence that CLS-B impact breast cancer risk or prognosis. Comparisons across studies of prognosis were complicated by differences in CLS-B evaluation and deficiencies in study design, which future studies should take into consideration. Breast adipose tissue inflammation provides a plausible explanation for the obesity-breast cancer association, but further study is needed to establish its role and whether markers such as CLS-B are clinically useful.
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Affiliation(s)
- Maret L. Maliniak
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA; (J.M.-K.); (T.L.L.); (L.E.M.)
| | - Jasmine Miller-Kleinhenz
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA; (J.M.-K.); (T.L.L.); (L.E.M.)
| | | | - Timothy L. Lash
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA; (J.M.-K.); (T.L.L.); (L.E.M.)
- Department of Clinical Epidemiology, Aarhus University Hospital, 8200 Aarhus, Denmark;
- Glenn Family Breast Center, Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA;
| | - Keerthi Gogineni
- Glenn Family Breast Center, Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA;
- Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Emiel A. M. Janssen
- Department of Pathology, Stavanger University Hospital, 4011 Stavanger, Norway;
| | - Lauren E. McCullough
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA; (J.M.-K.); (T.L.L.); (L.E.M.)
- Glenn Family Breast Center, Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA;
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37
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Hetemäki N, Mikkola TS, Tikkanen MJ, Wang F, Hämäläinen E, Turpeinen U, Haanpää M, Vihma V, Savolainen-Peltonen H. Adipose tissue estrogen production and metabolism in premenopausal women. J Steroid Biochem Mol Biol 2021; 209:105849. [PMID: 33610799 DOI: 10.1016/j.jsbmb.2021.105849] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 02/03/2021] [Accepted: 02/07/2021] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Although the ovaries produce the majority of estrogens in women before menopause, estrogen is also synthesized in peripheral tissues such as adipose tissue (AT). The typical female AT distribution, concentrated in subcutaneous and femoro-gluteal regions, is estrogen-mediated, but the significance of estrogen synthesis in AT of premenopausal women is poorly understood. DESIGN AND METHODS Serum and subcutaneous and visceral AT homogenates from 28 premenopausal women undergoing non-malignant surgery were analyzed for estrone, estradiol, and serum estrone sulfate (E1S) concentrations with liquid chromatography-tandem mass spectrometry. Isotopic precursors were used to measure enzyme activities of estrone-producing steroid sulfatase and estradiol-producing 17β-hydroxysteroid dehydrogenases (17β-HSD). Messenger RNA (mRNA) expression levels of genes for estrogen-metabolizing enzymes were analyzed using real-time reverse transcription quantitative polymerase chain reaction. RESULTS While estradiol was the predominant circulating active estrogen, estrone dominated in AT, with a higher concentration in visceral than subcutaneous AT (median, 2657 vs 1459 pmol/kg; P = 0.002). Both AT depots converted circulating E1S to estrone, and estrone to estradiol. Median levels of estrone were five to ten times higher in subcutaneous and visceral AT than in serum (P < 0.001) and the estradiol level in visceral AT was 1.3 times higher than in serum (P < 0.005). The local estrone concentration in visceral AT correlated positively with mRNA expression of estrone-producing enzyme aromatase (r = 0.65, P = 0.003). Waist circumference correlated positively with increased estradiol production in subcutaneous AT (r = 0.60, P = 0.039). CONCLUSIONS Premenopausal AT demonstrated high estrogenic enzyme activity and considerable local estrogen concentrations. This may be a factor promoting female-typical AT distribution in premenopausal women.
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Affiliation(s)
- Natalia Hetemäki
- Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, FIN-00029 HUS, Helsinki, Finland; Folkhälsan Research Center, University of Helsinki, FIN-00014, Helsinki, Finland
| | - Tomi S Mikkola
- Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, FIN-00029 HUS, Helsinki, Finland; Folkhälsan Research Center, University of Helsinki, FIN-00014, Helsinki, Finland
| | - Matti J Tikkanen
- Folkhälsan Research Center, University of Helsinki, FIN-00014, Helsinki, Finland; Heart and Lung Center, University of Helsinki and Helsinki University Hospital, FIN-00029 HUS, Helsinki, Finland
| | - Feng Wang
- Folkhälsan Research Center, University of Helsinki, FIN-00014, Helsinki, Finland
| | - Esa Hämäläinen
- Department of Clinical Chemistry, University of Helsinki, FIN-00029 HUS, Helsinki, Finland
| | - Ursula Turpeinen
- HUSLAB, Helsinki University Hospital, FIN-00029 HUS, Helsinki, Finland
| | - Mikko Haanpää
- HUSLAB, Helsinki University Hospital, FIN-00029 HUS, Helsinki, Finland
| | - Veera Vihma
- Folkhälsan Research Center, University of Helsinki, FIN-00014, Helsinki, Finland; Department of General Practice and Primary Health Care, University of Helsinki, FIN-00014, Helsinki, Finland
| | - Hanna Savolainen-Peltonen
- Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, FIN-00029 HUS, Helsinki, Finland; Folkhälsan Research Center, University of Helsinki, FIN-00014, Helsinki, Finland.
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38
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Escriche-Escuder A, Trinidad-Fernández M, Pajares B, Iglesias-Campos M, Alba E, Cuesta-Vargas AI, Roldán-Jiménez C. Ultrasound use in metastatic breast cancer to measure body composition changes following an exercise intervention. Sci Rep 2021; 11:8858. [PMID: 33893370 PMCID: PMC8065020 DOI: 10.1038/s41598-021-88375-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 04/12/2021] [Indexed: 01/04/2023] Open
Abstract
Changes in body composition and muscle dysfunction are common in metastatic breast cancer (MBC). Ultrasound imaging (US) offers reliable information about muscle and fat tissue architecture (thickness) and quality (echo-intensity). This study aimed to analyze the responsiveness of thickness and echo-intensity and its possible relationship with functional and patient reported-outcomes (PRO) in MBC patients after an exercise intervention. A prospective study was conducted in 2019. A 12-week exercise program was performed, including aerobic exercise and strength training. Measurements were made at baseline and after intervention. Thickness and echo-intensity were obtained from the quadriceps and biceps brachii and brachialis (BB). Mean differences were calculated using the T-Student parametric test for dependent samples of the differences in the means before and after the intervention (p = 0.05; 95% CI). Data from 13 MBC patients showed that some US muscle variables had significant differences after intervention. Best correlations were found between the quality of life questionnaire (QLQ-BR23) PRO and variables from BB muscle thickness in contraction (r = 0.61, p < 0.01), and Non-contraction (r = 0.55, p < 0.01). BB Muscle Non-contraction Thickness also explained 70% of QLQ-BR23 variance. In conclusion, muscle architecture biomarkers showed great responsiveness and are correlated with PRO after an exercise intervention in MBC patients.
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Affiliation(s)
- Adrian Escriche-Escuder
- Department of Physiotherapy, University of Malaga, C/Arquitecto Peñalosa, 3, 29071, Málaga, Spain
- Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain
| | - Manuel Trinidad-Fernández
- Department of Physiotherapy, University of Malaga, C/Arquitecto Peñalosa, 3, 29071, Málaga, Spain
- Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain
| | - Bella Pajares
- UGCI Oncológica Médica, Hospital Regional Universitario y Virgen de la Victoria, Málaga, Spain
| | - Marcos Iglesias-Campos
- UGCI Oncológica Médica, Hospital Regional Universitario y Virgen de la Victoria, Málaga, Spain
| | - Emilio Alba
- Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain
- UGCI Oncológica Médica, Hospital Regional Universitario y Virgen de la Victoria, Málaga, Spain
| | - Antonio I Cuesta-Vargas
- Department of Physiotherapy, University of Malaga, C/Arquitecto Peñalosa, 3, 29071, Málaga, Spain.
- Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain.
- School of Clinical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia.
| | - Cristina Roldán-Jiménez
- Department of Physiotherapy, University of Malaga, C/Arquitecto Peñalosa, 3, 29071, Málaga, Spain
- Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain
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39
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Kulkarni A, Bowers LW. The role of immune dysfunction in obesity-associated cancer risk, progression, and metastasis. Cell Mol Life Sci 2021; 78:3423-3442. [PMID: 33464384 PMCID: PMC11073382 DOI: 10.1007/s00018-020-03752-z] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 12/10/2020] [Accepted: 12/28/2020] [Indexed: 02/07/2023]
Abstract
Obesity has been linked to an increased risk of and a worse prognosis for several types of cancer. A number of interrelated mediators contribute to obesity's pro-tumor effects, including chronic adipose inflammation and other perturbations of immune cell development and function. Here, we review studies examining the impact of obesity-induced immune dysfunction on cancer risk and progression. While the role of adipose tissue inflammation in obesity-associated cancer risk has been well characterized, the effects of obesity on immune cell infiltration and activity within the tumor microenvironment are not well studied. In this review, we aim to highlight the impact of both adipose-mediated inflammatory signaling and intratumoral immunosuppressive signaling in obesity-induced cancer risk, progression, and metastasis.
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Affiliation(s)
- Aneesha Kulkarni
- Department of Nutrition Science, College of Health and Human Sciences, Purdue University, West Lafayette, IN, 47906, USA
| | - Laura W Bowers
- Department of Nutrition Science, College of Health and Human Sciences, Purdue University, West Lafayette, IN, 47906, USA.
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40
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Almekinders MMM, Schaapveld M, Thijssen B, Visser LL, Bismeijer T, Sanders J, Isnaldi E, Hofland I, Mertz M, Wessels LFA, Broeks A, Hooijberg E, Zwart W, Lips EH, Desmedt C, Wesseling J. Breast adipocyte size associates with ipsilateral invasive breast cancer risk after ductal carcinoma in situ. NPJ Breast Cancer 2021; 7:31. [PMID: 33753731 PMCID: PMC7985299 DOI: 10.1038/s41523-021-00232-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 02/03/2021] [Indexed: 12/25/2022] Open
Abstract
Although ductal carcinoma in situ (DCIS) is a non-obligate precursor to ipsilateral invasive breast cancer (iIBC), most DCIS lesions remain indolent. Hence, overdiagnosis and overtreatment of DCIS is a major concern. There is an urgent need for prognostic markers that can distinguish harmless from potentially hazardous DCIS. We hypothesised that features of the breast adipose tissue may be associated with risk of subsequent iIBC. We performed a case-control study nested in a population-based DCIS cohort, consisting of 2658 women diagnosed with primary DCIS between 1989 and 2005, uniformly treated with breast conserving surgery (BCS) alone. We assessed breast adipose features with digital pathology (HALO®, Indica Labs) and related these to iIBC risk in 108 women that developed subsequent iIBC (cases) and 168 women who did not (controls) by conditional logistic regression, accounting for clinicopathological and immunohistochemistry variables. Large breast adipocyte size was significantly associated with iIBC risk (odds ratio (OR) 2.75, 95% confidence interval (95% CI) = 1.25-6.05). High cyclooxygenase (COX)-2 protein expression in the DCIS cells was also associated with subsequent iIBC (OR 3.70 (95% CI = 1.59-8.64). DCIS with both high COX-2 expression and large breast adipocytes was associated with a 12-fold higher risk (OR 12.0, 95% CI = 3.10-46.3, P < 0.001) for subsequent iIBC compared with women with smaller adipocyte size and low COX-2 expression. Large breast adipocytes combined with high COX-2 expression in DCIS is associated with a high risk of subsequent iIBC. Besides COX-2, adipocyte size has the potential to improve clinical management in patients diagnosed with primary DCIS.
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Affiliation(s)
- Mathilde M M Almekinders
- Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands
- Department of Pathology, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
| | - Michael Schaapveld
- Division of Psychosocial Research, Epidemiology and Biostatistics, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Bram Thijssen
- Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Lindy L Visser
- Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Tycho Bismeijer
- Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Joyce Sanders
- Department of Pathology, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
| | - Edoardo Isnaldi
- Laboratory for Translational Breast Cancer Research, Department of Oncology, KU Leuven, Leuven, Belgium
- Department of Internal Medicine and Medical Specialties, Università degli Studi di Genova, IT-16132, Genova, Italy
| | - Ingrid Hofland
- Core Facility Molecular Pathology and Biobanking, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Marjolijn Mertz
- Bio-Imaging Facility, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Lodewyk F A Wessels
- Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, The Netherlands
- Oncode Institute, Utrecht, The Netherlands
| | - Annegien Broeks
- Core Facility Molecular Pathology and Biobanking, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Erik Hooijberg
- Department of Pathology, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
| | - Wilbert Zwart
- Oncode Institute, Utrecht, The Netherlands
- Division of Oncogenomics, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Esther H Lips
- Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Christine Desmedt
- Laboratory for Translational Breast Cancer Research, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Jelle Wesseling
- Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
- Department of Pathology, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
- Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
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The Tumor Promotional Role of Adipocytes in the Breast Cancer Microenvironment and Macroenvironment. THE AMERICAN JOURNAL OF PATHOLOGY 2021; 191:1342-1352. [PMID: 33639102 DOI: 10.1016/j.ajpath.2021.02.006] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Revised: 01/23/2021] [Accepted: 02/02/2021] [Indexed: 12/12/2022]
Abstract
The role of the adipocyte in the tumor microenvironment has received significant attention as a critical mediator of the obesity-cancer relationship. Current estimates indicate that 650 million adults have obesity, and thirteen cancers, including breast cancer, are estimated to be associated with obesity. Even in people with a normal body mass index, adipocytes are key players in breast cancer progression because of the proximity of tumors to mammary adipose tissue. Outside the breast microenvironment, adipocytes influence metabolic and immune function and produce numerous signaling molecules, all of which affect breast cancer development and progression. The current epidemiologic data linking obesity, and importantly adipose tissue, to breast cancer risk and prognosis, focusing on metabolic health, weight gain, and adipose distribution as underlying drivers of obesity-associated breast cancer is presented here. Bioactive factors produced by adipocytes, both normal and cancer associated, such as cytokines, growth factors, and metabolites, and the potential mechanisms through which adipocytes influence different breast cancer subtypes are highlighted.
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Molehin D, Rasha F, Rahman RL, Pruitt K. Regulation of aromatase in cancer. Mol Cell Biochem 2021; 476:2449-2464. [PMID: 33599895 DOI: 10.1007/s11010-021-04099-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Accepted: 02/04/2021] [Indexed: 12/21/2022]
Abstract
The regulation of aromatase, an enzyme involved in the biosynthesis of estrogen in normal and cancer cells, has been associated with growth factor signaling and immune response modulation. The tissue-specific regulatory roles of these factors are of particular importance as local aromatase expression is strongly linked to cancer development/progression and disease outcomes in patients. Therefore, aromatase has become a chemotherapeutic target and aromatase inhibitors (AIs) are used in the clinic for treating hormone-dependent cancers. Although AIs have shown promising results in the treatment of cancers, the emerging increase in AI-resistance necessitates the development of new and improved targeted therapies. This review discusses the role of tumor and stromal-derived growth factors and immune cell modulators in regulating aromatase. Current single-agent and combination therapies with or without AIs targeting growth factors and immune checkpoints are also discussed. This review highlights recent studies that show new connections between growth factors, mediators of immune response, and aromatase regulation.
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Affiliation(s)
- Deborah Molehin
- Department of Immunology & Molecular Microbiology, Texas Tech University Health Sciences Center, Lubbock, TX, USA
| | - Fahmida Rasha
- Department of Immunology & Molecular Microbiology, Texas Tech University Health Sciences Center, Lubbock, TX, USA
| | | | - Kevin Pruitt
- Department of Immunology & Molecular Microbiology, Texas Tech University Health Sciences Center, Lubbock, TX, USA. .,Department of Immunology & Molecular Microbiology, Texas Tech University Health Sciences Center, 3601 4th Street, Lubbock, TX, 79430-6591, USA.
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Scully T, Ettela A, LeRoith D, Gallagher EJ. Obesity, Type 2 Diabetes, and Cancer Risk. Front Oncol 2021; 10:615375. [PMID: 33604295 PMCID: PMC7884814 DOI: 10.3389/fonc.2020.615375] [Citation(s) in RCA: 108] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Accepted: 12/09/2020] [Indexed: 12/12/2022] Open
Abstract
Obesity and type 2 diabetes have both been associated with increased cancer risk and are becoming increasingly prevalent. Metabolic abnormalities such as insulin resistance and dyslipidemia are associated with both obesity and type 2 diabetes and have been implicated in the obesity-cancer relationship. Multiple mechanisms have been proposed to link obesity and diabetes with cancer progression, including an increase in insulin/IGF-1 signaling, lipid and glucose uptake and metabolism, alterations in the profile of cytokines, chemokines, and adipokines, as well as changes in the adipose tissue directly adjacent to the cancer sites. This review aims to summarize and provide an update on the epidemiological and mechanistic evidence linking obesity and type 2 diabetes with cancer, focusing on the roles of insulin, lipids, and adipose tissue.
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Affiliation(s)
- Tiffany Scully
- Division of Endocrinology, Diabetes and Bone Disease, Icahn School of Medicine at Mount Sinai, New York City, NY, United States
| | - Abora Ettela
- Division of Endocrinology, Diabetes and Bone Disease, Icahn School of Medicine at Mount Sinai, New York City, NY, United States
| | - Derek LeRoith
- Division of Endocrinology, Diabetes and Bone Disease, Icahn School of Medicine at Mount Sinai, New York City, NY, United States
- Tisch Cancer Institute at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York City, NY, United States
| | - Emily Jane Gallagher
- Division of Endocrinology, Diabetes and Bone Disease, Icahn School of Medicine at Mount Sinai, New York City, NY, United States
- Tisch Cancer Institute at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York City, NY, United States
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Melatonin as an Oncostatic Molecule Based on Its Anti-Aromatase Role in Breast Cancer. Int J Mol Sci 2021; 22:ijms22010438. [PMID: 33406787 PMCID: PMC7795758 DOI: 10.3390/ijms22010438] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 12/28/2020] [Accepted: 12/30/2020] [Indexed: 12/17/2022] Open
Abstract
Breast cancer is the most common type of cancer. In the developmental stages of breast cancer, estrogens are strongly involved. As estrogen synthesis is regulated by the enzyme aromatase, targeting the activity of this enzyme represents a therapeutic option. The pineal hormone melatonin may exert a suppressive role on aromatase activity, leading to reduced estrogen biosynthesis. A melatonin-mediated decrease in the expression of aromatase promoters and associated genes would provide suitable evidence of this molecule’s efficacy as an aromatase inhibitor. Furthermore, melatonin intensifies radiation-induced anti-aromatase effects and counteracts the unwanted disadvantages of chemotherapeutic agents. In this manner, this review summarizes the inhibitory role of melatonin in aromatase action, suggesting its role as a possible oncostatic molecule in breast cancer.
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Barros-Oliveira MDC, Costa-Silva DR, dos Santos AR, Pereira RO, Soares-Júnior JM, da Silva BB. Influence of CYP19A1 gene expression levels in women with breast cancer: a systematic review of the literature. Clinics (Sao Paulo) 2021; 76:e2846. [PMID: 34133482 PMCID: PMC8183338 DOI: 10.6061/clinics/2021/e2846] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Accepted: 05/06/2021] [Indexed: 01/22/2023] Open
Abstract
Breast cancer is the most frequently diagnosed malignant neoplasm in women and is considered a multifactorial disease of unknown etiology. One of the major risk factors is genetic alteration. Changes in CYP19A1 gene expression levels have been associated with increased risk and increased aggressiveness of breast cancer. Increased CYP19A1 gene expression and/or aromatase activity are among the major regulatory events for intratumoral production of estrogens in breast malignant tissues. This systematic review aimed to investigate the influence of CYP19A1 gene expression levels in women with breast cancer. The research was carried out using the PubMed, Scopus, and Web of Science databases. Searches were conducted between February 2 and May 15, 2019. Inclusion criteria were studies published between 2009 and 2019, English language publications, and human studies addressing the gene expression of CYP19A1 in breast cancer. A total of 6.068 studies were identified through PubMed (n=773), Scopus (n=2,927), and the Web of Science (n=2,368). After selecting and applying the inclusion and exclusion criteria, six articles were included in this systematic review. This systematic review provides evidence that increased or decreased levels of CYP19A1 gene expression may be related to pathological clinical factors of disease, MFS, OS, DFS, WATi, markers of metabolic function, concentrations of E1, FSH, and in the use of multiple exons 1 of the CYP19A1 gene in breast cancer.
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Affiliation(s)
- Maria da Conceição Barros-Oliveira
- Programa de Pos-Graduacao, Departamento de Saude, Rede Nordeste de Biotecnologia (RENORBIO), Universidade Federal do Piaui, Teresina, PI, BR
| | - Danylo Rafhael Costa-Silva
- Programa de Pos-Graduacao, Departamento de Saude, Rede Nordeste de Biotecnologia (RENORBIO), Universidade Federal do Piaui, Teresina, PI, BR
| | | | - Renato Oliveira Pereira
- Programa de Pos-Graduacao, Departamento de Saude, Rede Nordeste de Biotecnologia (RENORBIO), Universidade Federal do Piaui, Teresina, PI, BR
| | - José Maria Soares-Júnior
- Disciplina de Ginecologia, Departamento de Obstetricia e Ginecologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR
| | - Benedito Borges da Silva
- Programa de Pos-Graduacao, Departamento de Saude, Rede Nordeste de Biotecnologia (RENORBIO), Universidade Federal do Piaui, Teresina, PI, BR
- Hospital Getulio Vargas, Universidade Federal do Piaui, Teresina, PI, BR
- Corresponding author. E-mail:
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46
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Stasiewicz B, Wadolowska L, Biernacki M, Slowinska MA, Drozdowski M. Hybrid Dietary-Blood Inflammatory Profiles and Postmenopausal Breast Cancer: A Case-Control Study. Nutrients 2020; 12:nu12113503. [PMID: 33202561 PMCID: PMC7697398 DOI: 10.3390/nu12113503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 11/04/2020] [Accepted: 11/13/2020] [Indexed: 12/24/2022] Open
Abstract
The carcinogenesis process is associated with inflammation, which can be modified by diet. There is limited evidence regarding the inflammatory status and diet in association with breast cancer (BC). The aim of this study was to investigate the association of hybrid dietary-blood inflammatory profiles (HD-BIPs) with postmenopausal breast cancer occurrence. The case-control study was conducted among 420 women (230 controls, 190 primary BC cases) aged 40–79 years from north-eastern Poland. Blood levels of C-reactive protein (CRP), interleukin-6 (IL-6) and leukocyte count were marked in 129 postmenopausal women (82 controls, 47 cases). The 62-item food frequency questionnaire (FFQ-6) was used to the dietary data collection. Two HD-BIPs were found using the Principal Component Analysis (PCA). The “Pro-healthy/Neutral-inflammatory” profile was characterized by the frequent consumption of wholemeal cereals/coarse groats, legumes, vegetables, fruits, nuts/seeds and fish. The “Unhealthy/Pro-inflammatory” profile was characterized by the frequent consumption of red/processed meats, animal fats, sugar/honey/sweets, refined cereals/fine groats, and an increased concentration of CRP, IL-6 and granulocyte-to-lymphocyte ratio. The lower odds ratio (OR) of breast cancer was associated with the higher adherence to the “Pro-healthy/Neutral-inflammatory” profile (OR = 0.38; 95% Cl: 0.18–0.80; p < 0.01 for the higher level vs. lower level, crude model; OR for one-point score increment: 0.61; 95% Cl: 0.42–0.87; p < 0.01, adjusted model). The higher OR of breast cancer was associated with the higher adherence to the “Unhealthy/Pro-inflammatory” profile (OR = 3.07; 95%Cl: 1.27–7.44; p < 0.05 for the higher level v.s. lower level, adjusted model; OR for one-point score increment: 1.18; 95%Cl: 1.02–1.36; p < 0.05, adjusted model). This study revealed that the consumption of highly processed, high in sugar and animal fat foods should be avoided because this unhealthy diet was positively associated with postmenopausal breast cancer occurrence through its pro-inflammatory potential. Instead, the frequent consumption of low-processed plant foods and fish should be recommended since this pro-healthy diet was inversely associated with the cancer occurrence even though its anti-inflammatory potential has not been confirmed in this study sample.
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Affiliation(s)
- Beata Stasiewicz
- Department of Human Nutrition, Faculty of Food Sciences, University of Warmia and Mazury in Olsztyn, Sloneczna 45f, 10-718 Olsztyn, Poland; (L.W.); (M.A.S.)
- Correspondence: ; Tel.: +48-895245518
| | - Lidia Wadolowska
- Department of Human Nutrition, Faculty of Food Sciences, University of Warmia and Mazury in Olsztyn, Sloneczna 45f, 10-718 Olsztyn, Poland; (L.W.); (M.A.S.)
| | - Maciej Biernacki
- Department of Surgery, University of Warmia and Mazury in Olsztyn, 11-041 Olsztyn, Poland;
| | - Malgorzata Anna Slowinska
- Department of Human Nutrition, Faculty of Food Sciences, University of Warmia and Mazury in Olsztyn, Sloneczna 45f, 10-718 Olsztyn, Poland; (L.W.); (M.A.S.)
| | - Marek Drozdowski
- Department of Psychology and Sociology of Health and Public Health, School of Public Health, University of Warmia and Mazury in Olsztyn, 11-041 Olsztyn, Poland;
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47
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Shaik AN, Kiavash K, Stark K, Boerner JL, Ruterbusch JJ, Deirawan H, Bandyopadhyay S, Ali-Fehmi R, Dyson G, Cote ML. Inflammation markers on benign breast biopsy are associated with risk of invasive breast cancer in African American women. Breast Cancer Res Treat 2020; 185:831-839. [PMID: 33113091 DOI: 10.1007/s10549-020-05983-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 10/15/2020] [Indexed: 12/13/2022]
Abstract
PURPOSE Markers of inflammation, including crown-like structures of the breast (CLS-B) and infiltrating lymphocytes (IL), have been identified in breast tissue and associated with increased risk of breast cancer (BrCa), however most of this work has been performed in primarily non-Hispanic white women. Here, we examined whether CLS-B and IL are associated with invasive BrCa in African American (AA) women. METHODS We assessed breast biopsies from three 5-year age-matched groups: BrCa-free AA women (50 Volunteer) from the Komen Normal Tissue Bank (KTB) and AA women with a clinically-indicated biopsy diagnosed with benign breast disease (BBD) from our Detroit cohort who developed BrCa (55 BBD-cancer) or did not develop BrCa (47 BBD only, year of biopsy matched to BBD-cancer). Mean adipocyte diameter and total adipose area were estimated from digital images using the Adiposoft plugin from ImageJ. Associations between CLS-B, IL, and BrCa among KTB and Detroit biopsies were assessed using multivariable multinomial and conditional logistic regression models. RESULTS Among all biopsies, Volunteer and BBD only biopsies did not harbor CLS-B or IL at significantly different rates after adjusting for logarithm of adipocyte area, adipocyte diameter, and BMI. Among clinically-indicated BBD biopsies, BBD-cancer biopsies were more likely to exhibit CLS-B (odds ratio (OR) = 3.36, 95% Confidence Interval (CI): 1.33-8.48) or IL (OR = 4.95, 95% CI 1.76-13.9) than BBD only biopsies after adjusting for total adipocyte area, adipocyte diameter, proliferative disease, and BMI. CONCLUSIONS CLS-B and IL may serve as histological markers of BrCa risk in benign breast biopsies from AA women.
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Affiliation(s)
- Asra N Shaik
- Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA
| | - Katrin Kiavash
- Department of Pathology, Anatomy and Laboratory Medicine, West Virginia University School of Medicine, Morgantown, WV, USA
| | - Karri Stark
- Barbara Ann Karmanos Cancer Institute, 4100 John R. St, Mailstop: MM04EP, Detroit, MI, 48201, USA
| | - Julie L Boerner
- Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA.,Barbara Ann Karmanos Cancer Institute, 4100 John R. St, Mailstop: MM04EP, Detroit, MI, 48201, USA
| | - Julie J Ruterbusch
- Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA
| | - Hany Deirawan
- Department of Pathology, Wayne State University School of Medicine, Detroit, MI, USA.,Barbara Ann Karmanos Cancer Institute, 4100 John R. St, Mailstop: MM04EP, Detroit, MI, 48201, USA
| | - Sudeshna Bandyopadhyay
- Department of Pathology, Wayne State University School of Medicine, Detroit, MI, USA.,Barbara Ann Karmanos Cancer Institute, 4100 John R. St, Mailstop: MM04EP, Detroit, MI, 48201, USA
| | - Rouba Ali-Fehmi
- Department of Pathology, Wayne State University School of Medicine, Detroit, MI, USA.,Barbara Ann Karmanos Cancer Institute, 4100 John R. St, Mailstop: MM04EP, Detroit, MI, 48201, USA
| | - Gregory Dyson
- Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA.,Barbara Ann Karmanos Cancer Institute, 4100 John R. St, Mailstop: MM04EP, Detroit, MI, 48201, USA
| | - Michele L Cote
- Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA. .,Barbara Ann Karmanos Cancer Institute, 4100 John R. St, Mailstop: MM04EP, Detroit, MI, 48201, USA.
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Yang Y, Kelifa MO, Yu B, Herbert C, Wang Y, Jiang J. Gender-specific temporal trends in overweight prevalence among Chinese adults: a hierarchical age-period-cohort analysis from 2008 to 2015. Glob Health Res Policy 2020; 5:42. [PMID: 32944654 PMCID: PMC7488461 DOI: 10.1186/s41256-020-00169-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Accepted: 08/26/2020] [Indexed: 01/22/2023] Open
Abstract
Background As a key health risk, the prevalence of overweight has been strikingly increasing worldwide. This study aimed to disentangle the net age, period, and cohort effects on overweight among Chinese adults by gender. Methods Data came from the Chinese General Social Survey from 2008 to 2015, which was a repeated cross-sectional survey (n = 55,726, aged 18 and older). χ2 or t tests were used to estimate the gender disparities in overweight and socioeconomic status (SES). A series of hierarchical age-period-cohort cross-classified random-effects models were performed using SAS version 9.4 to estimate the overall and gender-specific temporal trends of overweight, as well as the association between SES and overweight. Further, a series of line charts were used to present the age and cohort variations in overweight. Results After controlling for covariates, significant age and cohort effects were observed among adults in China (b = 0.0205, p < 0.001; b = 0.0122, p < 0.05; respectively). Specifically, inverted U-shaped age effects were identified for both genders, with a high probability of overweight occurring in middle age (b = -0.0012, p < 0.001). Overweight was more prevalent among men than women before 60 years old, and this trend reversed thereafter (b = -0.0253, p < 0.001). Moreover, men born during the war (before 1950) and reform cohorts (after the 1975s) demonstrated a substantial decline in overweight, while men born in 1950-1975 showed an increasing trend in overweight prevalence (b = 0.0378, p < 0.05). However, the cohort effect on women was not statistically significant. Additionally, a higher SES was related to an elevated probability of overweight. Conclusion Gender-specific age and cohort effects on the prevalence of overweight were observed among Chinese adults. Both China and other developing countries need to pay attention to the coming obesity challenge and related health inequality. Full life-cycle overweight prevention interventions should focus on middle-aged adults, men born in the war and reform eras, and adults with a higher SES.
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Affiliation(s)
- Yinmei Yang
- School of Health Sciences, Wuhan University, 115 Donghu Road, Wuhan, 430071 Hubei China
| | | | - Bin Yu
- Department of Epidemiology, University of Florida, 2004 Mowry Road, Gainesville, FL 100231 USA
| | - Carly Herbert
- University of Massachusetts Medical School, Worcester, MA USA
| | - Yongbo Wang
- School of Health Sciences, Wuhan University, 115 Donghu Road, Wuhan, 430071 Hubei China
| | - Junfeng Jiang
- School of Health Sciences, Wuhan University, 115 Donghu Road, Wuhan, 430071 Hubei China
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Associations between markers of mammary adipose tissue dysfunction and breast cancer prognostic factors. Int J Obes (Lond) 2020; 45:195-205. [PMID: 32934318 DOI: 10.1038/s41366-020-00676-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 09/03/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Obesity fosters worse clinical outcomes in both premenopausal and postmenopausal women with breast cancer. Emerging evidence suggests that an android body fat distribution in particular is deleterious for breast cancer prognosis. The extent of adipose tissue dysfunction, especially how it relates to breast cancer prognostic factors and anthropometric measurements, has not been fully investigated. OBJECTIVE Our objective was to examine if markers of adipose tissue dysfunction, such as hypertrophy and macrophage accumulation, are relevant for the pathophysiology of breast cancer and its associated prognostic factors in a well-characterised cohort of women with breast cancer who did not receive treatment before surgery. METHODS A consecutive series of 164 women with breast cancer provided breast adipose tissue sample. Multivariate generalised linear models were used to test associations of anthropometric indices and prognostic factors with markers of adipose tissue dysfunction. RESULTS We found associations of breast adipocyte size and macrophage infiltration (number of CD68+ cells/100 adipocytes) with adiposity, particularly a strong association between breast adipocyte size and central obesity, independent of total adiposity, age and menopausal status (βadj = 0.87; p = 0.0001). We also identified relationships of adipocyte hypertrophy and macrophage infiltration with prognostic factors, such as cancer stage and tumour grade (p < 0.05). RNA expression of pro-inflammatory cytokines (IL6, TNF) and leptin was also increased as a function of adipocyte size and CD86+/CD11c+ macrophage number/100 adipocytes (p < 0.05). CONCLUSIONS Our findings support the model of dysfunctional adipose tissue in obesity-associated breast cancer.
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50
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Neoadjuvant chemotherapy modifies serum pyrrolidone carboxypeptidase specific activity in women with breast cancer and influences circulating levels of GnRH and gonadotropins. Breast Cancer Res Treat 2020; 182:751-760. [PMID: 32506336 DOI: 10.1007/s10549-020-05723-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Accepted: 06/02/2020] [Indexed: 12/22/2022]
Abstract
PURPOSE Functional studies have demonstrated that gonadotropin-releasing hormone (GnRH) regulates cell proliferation, apoptosis, and tissue remodeling. GnRH is metabolized by the proteolytic regulatory enzyme pyrrolidone carboxypeptidase (Pcp) (E.C. 3.4.19.3), which is an omega peptidase widely distributed in fluids and tissues. We previously reported a decrease in both rat and human Pcp activity in breast cancer, suggesting that GnRH may be an important local hormonal factor in the pathogenesis of breast cancer. Recently, we have described that postmenopausal women with breast cancer show lower levels of serum Pcp activity than control postmenopausal women. To determine the effect of neoadjuvant chemotherapy (NACT) on serum Pcp specific activity and circulating levels of GnRH, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and steroid hormones 17-ß-estradiol and progesterone in pre- and postmenopausal women diagnosed with infiltrating ductal carcinoma. METHODS Serum Pcp activity was measured fluorometrically using pyroglutamyl-ß-naphthylamide. Circulating GnRH levels were dosed using a commercial RIA kit. Circulating LH and FSH levels were measured by enzyme immunoassays. Levels of steroid hormones were measured in serum samples by dissociation-enhanced lanthanide fluorescence immunoassay. RESULTS AND CONCLUSION Our results show the effect of NACT on the hypothalamic-pituitary axis, with the consequent alteration of circulating gonadotropins in premenopausal women with breast cancer. However, the results obtained in postmenopausal women with breast cancer treated with NACT, that is, the significant decrease in the concentration of GnRH and FSH compared to control postmenopausal women, differ from those obtained for premenopausal women. The only difference between pre- and postmenopausal women is their hormonal profile at the beginning of the study, that is, the presence of menopause and the consequent alteration of the hypothalamic-pituitary-gonadal axis.
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