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Dyachenko EI, Bel’skaya LV. Transmembrane Amino Acid Transporters in Shaping the Metabolic Profile of Breast Cancer Cell Lines: The Focus on Molecular Biological Subtype. Curr Issues Mol Biol 2024; 47:4. [PMID: 39852119 PMCID: PMC11763447 DOI: 10.3390/cimb47010004] [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: 11/29/2024] [Revised: 12/20/2024] [Accepted: 12/24/2024] [Indexed: 01/26/2025] Open
Abstract
Amino acid metabolism in breast cancer cells is unique for each molecular biological subtype of breast cancer. In this review, the features of breast cancer cell metabolism are considered in terms of changes in the amino acid composition due to the activity of transmembrane amino acid transporters. In addition to the main signaling pathway PI3K/Akt/mTOR, the activity of the oncogene c-Myc, HIF, p53, GATA2, NF-kB and MAT2A have a direct effect on the amino acid metabolism of cancer cells, their growth and proliferation, as well as the maintenance of homeostatic equilibrium. A distinctive feature of luminal subtypes of breast cancer from TNBC is the ability to perform gluconeogenesis. Breast cancers with a positive expression of the HER2 receptor, in contrast to TNBC and luminal A subtype, have a distinctive active synthesis and consumption of fatty acids. It is interesting to note that amino acid transporters exhibit their activity depending on the pH level inside the cell. In the most aggressive forms of breast cancer or with the gradual progression of the disease, pH will also change, which will directly affect the metabolism of amino acids. Using the cell lines presented in this review, we can trace the characteristic features inherent in each of the molecular biological subtypes of breast cancer and develop the most optimal therapeutic targets.
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Affiliation(s)
| | - Lyudmila V. Bel’skaya
- Biochemistry Research Laboratory, Omsk State Pedagogical University, 644099 Omsk, Russia;
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Önder T, Ateş Ö, Öner İ, Karaçin C. Triglyceride-Glucose Index: A Candidate Prognostic Marker in HR-Positive/HER2-Negative Metastatic Breast Cancer Patients Treated With CDK4/6 Inhibitors. Clin Breast Cancer 2024; 24:519-526. [PMID: 38879437 DOI: 10.1016/j.clbc.2024.05.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Revised: 04/26/2024] [Accepted: 05/07/2024] [Indexed: 07/28/2024]
Abstract
AIMS AND OBJECTIVES Although cyclin-dependent kinase 4/6 inhibitors (CDK 4/6i) are a vital part of the treatment of hormone receptor (HR)-positive/HER-2-negative metastatic breast cancer (BC), individuals have different sensitivities to CDK4/6i, indicating the need for biomarkers. The fasting triglyceride glucose (TyG) index is an easily accessible surrogate marker of insulin resistance (IR). Herein, we investigated the prognostic significance of the fasting triglyceride glucose (TyG) index in HR+/HER2- metastatic BC patients treated with CDK4/6i plus endocrine therapy (ET). METHODS About 333 patients with HR+/HER2-metastatic BC treated with CDK4/6i plus ET were analyzed retrospectively. The TyG index was calculated within 3 months before the initiation of CDK4/6i plus ET. The median value of 8.43 was taken as the cutoff for the TyG index. RESULTS The median overall survival (OS) was 73.6 months (95% CI, 66.0-81.1) in the whole cohort. The progression-free survival (PFS) was significantly longer in the low-TyG subgroup than in the high-TyG subgroup (30.1 vs. 21.3 months, multivariate adjusted [HR] = 0.666, 95% CI, 0.450-0.987, P = .043). While the median OS was not reached in the low TyG subgroup, it was 69.0 months in the high TyG subgroup (multivariate-adjusted HR = 0.513, 95% CI, 0.281-0.936, P = .030). Although the ORR and DCR were numerically greater in the low-TyG subgroup, no significant differences were observed between the low-TyG subgroup and high-TyG subgroup (28.1% vs. 24.7%, P = .476; 83.2% vs. 80.1%, P = .463, respectively). CONCLUSIONS These data imply that the TyG index could be a predictive biomarker for the therapeutic efficacy of CDK4/6is. Extensive prospective studies are needed to confirm these findings.
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Affiliation(s)
- Tuğba Önder
- Health Sciences University, Dr Abdurrahman Yurtaslan Ankara Oncology Education and Research Hospital, Department of Medical Oncology, Yenimahalle Ankara, Turkey.
| | - Öztürk Ateş
- Health Sciences University, Dr Abdurrahman Yurtaslan Ankara Oncology Education and Research Hospital, Department of Medical Oncology, Yenimahalle Ankara, Turkey
| | - İrem Öner
- Health Sciences University, Dr Abdurrahman Yurtaslan Ankara Oncology Education and Research Hospital, Department of Medical Oncology, Yenimahalle Ankara, Turkey
| | - Cengiz Karaçin
- Health Sciences University, Dr Abdurrahman Yurtaslan Ankara Oncology Education and Research Hospital, Department of Medical Oncology, Yenimahalle Ankara, Turkey
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Das C, Bhattacharya A, Adhikari S, Mondal A, Mondal P, Adhikary S, Roy S, Ramos K, Yadav KK, Tainer JA, Pandita TK. A prismatic view of the epigenetic-metabolic regulatory axis in breast cancer therapy resistance. Oncogene 2024; 43:1727-1741. [PMID: 38719949 PMCID: PMC11161412 DOI: 10.1038/s41388-024-03054-9] [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: 12/15/2023] [Revised: 04/23/2024] [Accepted: 04/24/2024] [Indexed: 06/09/2024]
Abstract
Epigenetic regulation established during development to maintain patterns of transcriptional expression and silencing for metabolism and other fundamental cell processes can be reprogrammed in cancer, providing a molecular mechanism for persistent alterations in phenotype. Metabolic deregulation and reprogramming are thus an emerging hallmark of cancer with opportunities for molecular classification as a critical preliminary step for precision therapeutic intervention. Yet, acquisition of therapy resistance against most conventional treatment regimens coupled with tumor relapse, continue to pose unsolved problems for precision healthcare, as exemplified in breast cancer where existing data informs both cancer genotype and phenotype. Furthermore, epigenetic reprograming of the metabolic milieu of cancer cells is among the most crucial determinants of therapeutic resistance and cancer relapse. Importantly, subtype-specific epigenetic-metabolic interplay profoundly affects malignant transformation, resistance to chemotherapy, and response to targeted therapies. In this review, we therefore prismatically dissect interconnected epigenetic and metabolic regulatory pathways and then integrate them into an observable cancer metabolism-therapy-resistance axis that may inform clinical intervention. Optimally coupling genome-wide analysis with an understanding of metabolic elements, epigenetic reprogramming, and their integration by metabolic profiling may decode missing molecular mechanisms at the level of individual tumors. The proposed approach of linking metabolic biochemistry back to genotype, epigenetics, and phenotype for specific tumors and their microenvironment may thus enable successful mechanistic targeting of epigenetic modifiers and oncometabolites despite tumor metabolic heterogeneity.
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Affiliation(s)
- Chandrima Das
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata, 700064, India.
- Homi Bhabha National Institute, Mumbai, 400094, India.
| | - Apoorva Bhattacharya
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata, 700064, India
| | - Swagata Adhikari
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata, 700064, India
- Homi Bhabha National Institute, Mumbai, 400094, India
| | - Atanu Mondal
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata, 700064, India
- Homi Bhabha National Institute, Mumbai, 400094, India
| | - Payel Mondal
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata, 700064, India
- Homi Bhabha National Institute, Mumbai, 400094, India
| | - Santanu Adhikary
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata, 700064, India
- Structural Biology and Bioinformatics Division, Council of Scientific and Industrial Research (CSIR)-Indian Institute of Chemical Biology, Kolkata, 700032, India
| | - Siddhartha Roy
- Structural Biology and Bioinformatics Division, Council of Scientific and Industrial Research (CSIR)-Indian Institute of Chemical Biology, Kolkata, 700032, India
| | - Kenneth Ramos
- Center for Genomics and Precision Medicine, Texas A&M University, School of Medicine, Houston, TX, 77030, USA
| | - Kamlesh K Yadav
- Center for Genomics and Precision Medicine, Texas A&M University, School of Medicine, Houston, TX, 77030, USA
- School of Engineering Medicine, Texas A&M University, School of Medicine, Houston, TX, 77030, USA
| | - John A Tainer
- The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
| | - Tej K Pandita
- Center for Genomics and Precision Medicine, Texas A&M University, School of Medicine, Houston, TX, 77030, USA.
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Mohammadzadeh M, Bahrami A, Abdi F, Ghafouri-Taleghani F, Paydareh A, Jalali S, Heidari Z, Rashidkhani B. Dietary Diabetes Risk Reduction Score (DDRRS) and Breast Cancer Risk: A Case-Control Study in Iran. Nutr Cancer 2023; 76:106-113. [PMID: 37986034 DOI: 10.1080/01635581.2023.2281025] [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: 07/27/2023] [Revised: 11/03/2023] [Accepted: 11/03/2023] [Indexed: 11/22/2023]
Abstract
INTRODUCTION Given the role of type 2 diabetes and insulin resistance in tumor initiation, we hypothesized that following a diet that reduces the risk of type 2 diabetes could also reduce the risk of breast cancer. Herein, we conducted a case-control study to investigate the association between dietary diabetes risk reduction score and breast cancer risk in Iranian women. METHOD We recruited 136 newly diagnosed cases and 272 age-matched hospitalized controls from referral hospitals. A valid and reliable 168-item food frequency questionnaire (FFQ) was used to collect the data on dietary intake. We used Multivariate Logistic regression to assess the odds ratio (OR) with 95% confidence interval (CI) of breast cancer by the dietary diabetes risk reduction score tertiles. RESULTS After adjusting for confounding variables, no association was seen between dietary diabetes risk reduction score and breast cancer risk (OR = 0.65, 95% CI: 0.37-1.14). However, after stratification by menopausal status, a decreased risk was observed between adherence to dietary diabetes risk reduction score and breast cancer risk in postmenopausal individuals (OR = 0.43, 95% CI: 0.19-0.99). CONCLUSION The present study states that there is no significant relationship between the dietary diabetes risk reduction score and the risk of breast cancer. However, adherence to dietary diabetes risk reduction score could have a preventive role for breast cancer among postmenopausal women.
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Affiliation(s)
- Milad Mohammadzadeh
- Department of Clinical Nutrition and Dietetics, Faculty of Nutrition Sciences and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Alireza Bahrami
- Department of Clinical Nutrition and Dietetics, Faculty of Nutrition Sciences and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fatemeh Abdi
- Department of Nutrition, Faculty of Nutrition and Food Science, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fatemeh Ghafouri-Taleghani
- Department of Clinical Nutrition and Dietetics, Faculty of Nutrition Sciences and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amin Paydareh
- Department of Clinical Nutrition and Dietetics, Faculty of Nutrition Sciences and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Saba Jalali
- Faculty of Land and Food Systems, University of British Colombia Vancouver, Vancouver, Canada
| | - Zeinab Heidari
- Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Bahram Rashidkhani
- Department of Community Nutrition, Faculty of Nutrition and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Stella S, Massimino M, Manzella L, Parrinello NL, Vitale SR, Martorana F, Vigneri P. Glucose-dependent effect of insulin receptor isoforms on tamoxifen antitumor activity in estrogen receptor-positive breast cancer cells. Front Endocrinol (Lausanne) 2023; 14:1081831. [PMID: 37361518 PMCID: PMC10289407 DOI: 10.3389/fendo.2023.1081831] [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: 10/27/2022] [Accepted: 05/23/2023] [Indexed: 06/28/2023] Open
Abstract
Introduction Breast cancer is the most common malignancy in women, and it is linked to several risk factors including genetic alterations, obesity, estrogen signaling, insulin levels, and glucose metabolism deregulation. Insulin and Insulin-like growth factor signaling exert a mitogenic and pro-survival effect. Indeed, epidemiological and pre-clinical studies have shown its involvement in the development, progression, and therapy resistance of several cancer types including breast cancer. Insulin/Insulin-like growth factor signaling is triggered by two insulin receptor isoforms identified as IRA and IRB and by Insulin-like growth factor receptor I. Both classes of receptors show high homology and can initiate the intracellular signaling cascade alone or by hybrids formation. While the role of Insulin-like growth factor receptor I in breast cancer progression and therapy resistance is well established, the effects of insulin receptors in this context are complex and not completely elucidated. Methods We used estrogen-dependent insulin-like growth factor receptor I deleted gene (MCF7IGFIRKO) breast cancer cell models, lentivirally transduced to over-express empty-vector (MCF7IGFIRKO/EV), IRA (MCF7IGFIRKO/IRA) or IRB (MCF7IGFIRKO/IRB), to investigate the role of insulin receptors on the antiproliferative activity of tamoxifen in presence of low and high glucose concentrations. The tamoxifen-dependent cytotoxic effects on cell proliferation were determined by MTT assay and clonogenic potential measurement. Cell cycle and apoptosis were assessed by FACS, while immunoblot was used for protein analysis. Gene expression profiling was investigated by a PCR array concerning genes involved in apoptotic process by RT-qPCR. Results We found that glucose levels played a crucial role in tamoxifen response mediated by IRA and IRB. High glucose increased the IC50 value of tamoxifen for both insulin receptors and IRA-promoted cell cycle progression more than IRB, independently of glucose levels and insulin stimulation. IRB, in turn, showed anti-apoptotic properties, preserving cells' survival after prolonged tamoxifen exposure, and negatively modulated pro-apoptotic genes when compared to IRA. Discussion Our findings suggest that glucose levels modify insulin receptors signaling and that this event can interfere with the tamoxifen therapeutic activity. The investigation of glucose metabolism and insulin receptor expression could have clinical implications in Estrogen Receptor positive breast cancer patients receiving endocrine treatments.
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Affiliation(s)
- Stefania Stella
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
- Center of Experimental Oncology and Hematology, Azienda Ospedaliera Universitaria (A.O.U.) Policlinico “G. Rodolico - San Marco”, Catania, Italy
| | - Michele Massimino
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
- Center of Experimental Oncology and Hematology, Azienda Ospedaliera Universitaria (A.O.U.) Policlinico “G. Rodolico - San Marco”, Catania, Italy
| | - Livia Manzella
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
- Center of Experimental Oncology and Hematology, Azienda Ospedaliera Universitaria (A.O.U.) Policlinico “G. Rodolico - San Marco”, Catania, Italy
| | - Nunziatina Laura Parrinello
- Division of Hematology, Azienda Ospedaliera Universitaria (A.O.U.) Policlinico “G. Rodolico-S. Marco”, Catania, Italy
| | - Silvia Rita Vitale
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
- Center of Experimental Oncology and Hematology, Azienda Ospedaliera Universitaria (A.O.U.) Policlinico “G. Rodolico - San Marco”, Catania, Italy
| | - Federica Martorana
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
- Center of Experimental Oncology and Hematology, Azienda Ospedaliera Universitaria (A.O.U.) Policlinico “G. Rodolico - San Marco”, Catania, Italy
| | - Paolo Vigneri
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
- Center of Experimental Oncology and Hematology, Azienda Ospedaliera Universitaria (A.O.U.) Policlinico “G. Rodolico - San Marco”, Catania, Italy
- University Oncology Department, Humanitas Istituto Clinico Catanese, Catania, Italy
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Ahmadirad H, Teymoori F, Nateghi R, Shabanian A, Mirmiran P. The Association of Empirical Dietary Index for Hyperinsulinemia with the Risk of Cancer and Cancer Mortality: A Meta-analysis of Observational Studies. Nutr Cancer 2023:1-14. [PMID: 37155247 DOI: 10.1080/01635581.2023.2189042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/10/2023]
Abstract
This meta-analysis aimed to assess the association between the empirical dietary index for hyperinsulinemia (EDIH) and cancer mortality risk. We performed a comprehensive search across the online literature up to November 2022 databases. Then, hazard ratio (H.R.) and 95% confidence intervals (CI) were extracted. A total of 14 and seven cohort studies that reported H.R. for the risk of cancer incidence and cancer mortality respectively were included. The pooled H.R. (95% CI) of the association between EDIH and cancer incidence was 1.13 (1.05-1.23) in overall meta-analyses, 1.15 (1.08-1.22) in female subgroups, 1.27 (1.14-1.41) in digestive cancer subgroups, and 1.15 (1.07-1.24) in breast cancer subgroups. Also, the pooled H.R. (95% CI) of the association between EDIH and incidence of cancer mortality was 1.19 (1.13-1.26) in overall meta-analyses, 1.23 (1.13-1.34) in males, 1.18(1.10-1.28) in females, and 1.20 (1.13-1.27) in studies conducted on all cancers as an outcome. Our findings revealed that a higher EDIH was significantly associated with an increased risk of cancer incidence, particularly in females, digestive cancers, and breast cancer. Also, a higher EDIH score was related to a higher risk of cancer mortality overall in both male and female subgroups and with all cancers.
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Affiliation(s)
- Hamid Ahmadirad
- Nutrition and Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Farshad Teymoori
- Nutrition and Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Department of Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran, Iran
| | - Reyhane Nateghi
- Department of Clinical Nutrition and Dietetics, Faculty of Nutrition and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Arman Shabanian
- Department of Food Science and Technology, Faculty of Nutrition Science, Food Science and Technology/National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Parvin Mirmiran
- Nutrition and Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Melnik BC, John SM, Carrera-Bastos P, Cordain L, Leitzmann C, Weiskirchen R, Schmitz G. The Role of Cow's Milk Consumption in Breast Cancer Initiation and Progression. Curr Nutr Rep 2023; 12:122-140. [PMID: 36729355 PMCID: PMC9974716 DOI: 10.1007/s13668-023-00457-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/06/2022] [Indexed: 02/03/2023]
Abstract
PURPOSE OF REVIEW This review evaluates cow milk's impact on breast carcinogenesis by linking recent epidemiological evidence and new insights into the molecular signaling of milk and its constituents in breast cancer (BCa) pathogenesis. RECENT FINDINGS Recent prospective cohort studies support the association between cow's milk consumption and the risk of estrogen receptor-α-positive (ER+) BCa. Milk is a complex biological fluid that increases systemic insulin-like growth factor 1 (IGF-1), insulin and estrogen signaling, and interacting hormonal promoters of BCa. Further potential oncogenic components of commercial milk include exosomal microRNAs (miR-148a-3p, miR-21-5p), bovine meat and milk factors, aflatoxin M1, bisphenol A, pesticides, and micro- and nanoplastics. Individuals with BRCA1 loss-of-function mutations and FTO and IGF1 gain-of-function polymorphisms enhancing IGF-1/mTORC1 signaling may be at increased risk for milk-induced ER+ BCa. Recent prospective epidemiological and pathobiochemical studies identify commercial milk consumption as a critical risk factor of ER+ BCa. Large meta-analyses gathering individuals of different ethnic origins with milk derived from dairy cows of varying genetic backgrounds and diverse feeding procedures as well as missing data on thermal processing of milk (pasteurization versus ultra-heat treatment) make multi-national meta-analyses unsuitable for BCa risk estimations in susceptible populations. Future studies are required that consider all vulnerable periods of breast carcinogenesis to cow's milk exposure, beginning during the perinatal period and puberty, since these are the most critical periods of mammary gland morphogenesis. Notwithstanding the need for better studies including detailed information on milk processing and vulnerable periods of human breast carcinogenesis, the available evidence suggests that dietary guidelines on milk consumption may have to be reconsidered.
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Affiliation(s)
- Bodo C Melnik
- Department of Dermatology, Environmental Medicine and Health Theory, University of Osnabrück, D-49076, Osnabrück, Germany.
| | - Swen Malte John
- Department of Dermatology, Environmental Medicine and Health Theory, University of Osnabrück, D-49076, Osnabrück, Germany
- Institute for Interdisciplinary Dermatological Prevention and Rehabilitation (iDerm) at the University of Osnabrück, Lower-Saxonian Institute of Occupational Dermatology (NIB), Osnabrück, Germany
| | - Pedro Carrera-Bastos
- Center for Primary Health Care Research, Lund University/Region Skåne, Skåne University Hospital, 205 02, Malmö, Sweden
- Faculty of Biomedical and Health Sciences, Universidad Europea de Madrid, 28670, Madrid, Spain
- Centro de Estudios Avanzados en Nutrición (CEAN), 11007, Cádiz, Spain
| | | | - Claus Leitzmann
- Institute of Nutrition, University of Giessen, 35390, Giessen, Germany
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, D-52074, Aachen, Germany
| | - Gerd Schmitz
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital of Regensburg, University of Regensburg, D-93053, Regensburg, Germany
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Powell M, Fuller S, Gunderson E, Benz C. A common IGF1R gene variant predicts later life breast cancer risk in women with preeclampsia. Breast Cancer Res Treat 2023; 197:149-159. [PMID: 36331687 PMCID: PMC9823040 DOI: 10.1007/s10549-022-06789-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 10/26/2022] [Indexed: 11/06/2022]
Abstract
PURPOSE Preeclampsia has been inconsistently associated with altered later life risk of cancer. This study utilizes the Nurses' Health Study 2 (NHS2) to determine if the future risk of breast and non-breast cancers in women who experience preeclampsia is modified by carrying a protective variant of rs2016347, a functional insulin-like growth factor receptor-1 (IGF1R) single nucleotide polymorphism. METHODS This retrospective cohort study completed within the NHS2 evaluated participants enrolled in 1989 and followed them through 2015, with a study population of 86,751 after exclusions. Cox proportional hazards models both with and without the impact of rs2016347 genotype were used to assess the risk of invasive breast cancer, hormone receptor-positive (HR+) breast cancer, and non-breast cancers. RESULTS Women with preeclampsia had no change in risk of all breast, HR+ breast, or non-breast cancers when not considering genotype. However, women carrying at least one T allele of rs2016347 had a lower risk of HR+ breast cancer, HR 0.67, 95% CI: 0.47-0.97, P = 0.04, with interaction term P = 0.06. For non-breast cancers as a group, women carrying a T allele had an HR 0.76, 95% CI: 0.53-1.08, P = 0.12, with interaction term P = 0.26. CONCLUSIONS This retrospective cohort study found that women with preeclampsia who carry a T allele of IGF1R rs2016347 had a reduced future risk of developing HR+ breast cancer, and a reduced but not statistically significant decreased risk of non-breast cancers suggesting a possible role for the IGF-1 axis in the development of cancer in these women.
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Affiliation(s)
- Mark Powell
- grid.272799.00000 0000 8687 5377Buck Institute for Research On Aging, 8001 Redwood Blvd, Novato, CA 94945 USA
| | - Sophia Fuller
- grid.47840.3f0000 0001 2181 7878Graduate Group in Biostatistics, School of Public Health, University of California, Berkeley, CA USA
| | - Erica Gunderson
- grid.280062.e0000 0000 9957 7758Division of Research, Kaiser Permanente Northern California, Oakland, CA USA
| | - Christopher Benz
- grid.272799.00000 0000 8687 5377Buck Institute for Research On Aging, 8001 Redwood Blvd, Novato, CA 94945 USA
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Gallagher EJ, Greco G, Lin S, Yagnik R, Feldman SM, Port E, Friedman NB, Boolbol SK, Killelea B, Pilewskie M, Choi L, LeRoith D, Bickell NA. Insulin resistance and racial disparities in breast cancer prognosis: a multi-center cohort study. Endocr Relat Cancer 2022; 29:693-701. [PMID: 36197762 PMCID: PMC9696320 DOI: 10.1530/erc-22-0106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Accepted: 09/30/2022] [Indexed: 11/07/2022]
Abstract
The survival for breast cancer (BC) is improving but remains lower in Black women than White women. A number of factors potentially drive the racial differences in BC outcomes. The aim of our study was to determine if insulin resistance (defined as homeostatic model assessment for insulin resistance (HOMA-IR)), mediated part of the relationship between race and BC prognosis (defined by the improved Nottingham prognostic index (iNPI)). We performed a cross-sectional study, recruiting self-identified Black and White women with newly diagnosed primary invasive BC from 10 US hospitals between March 2013 and February 2020. Survey, anthropometric, laboratory, and tumor pathology data were gathered, and we compared the results between Black and White women. We calculated HOMA-IR as well as iNPI scores and examined the associations between HOMA-IR and iNPI. After exclusions, the final cohort was 1206: 911 (76%) White and 295 (24%) Black women. Metabolic syndrome and insulin resistance were more common in Black than White women. Black women had less lobular BC, three times more triple-negative BC, and BCs with higher stage and iNPI scores than White women (P < 0.001 for all comparisons). Fewer Black women had BC genetic testing performed. HOMA-IR mediated part of the association between race and iNPI, particularly in BCs that carried a good prognosis and were hormone receptor (HR)-positive. Higher HOMA-IR scores were associated with progesterone receptor-negative BC in White women but not Black women. Overall, our results suggest that HOMA-IR contributes to the racial disparities in BC outcomes, particularly for women with HR-positive BCs.
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Affiliation(s)
- Emily J. Gallagher
- Division of Endocrinology, Diabetes and Bone Disease, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, USA
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, USA
- Tisch Cancer Institute at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Giampaolo Greco
- Department of Population Health Science and Policy, Center for Health Equity and Community Engaged Research, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Sylvia Lin
- Department of Population Health Science and Policy, Center for Health Equity and Community Engaged Research, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Radhi Yagnik
- Department of Population Health Science and Policy, Center for Health Equity and Community Engaged Research, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Sheldon M. Feldman
- Department of Surgery, Montefiore Medical Center, Albert Einstein College of Medicine, New York, NY, USA
| | - Elisa Port
- Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | | | - Susan K. Boolbol
- Department of Surgery, Mount Sinai Beth Israel, New York, NY, USA
| | - Brigid Killelea
- Department of Surgery, Yale School of Medicine, New Haven, CT, USA
| | - Melissa Pilewskie
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Lydia Choi
- Department of Surgery, Wayne State University School of Medicine, Detroit, MI, USA
| | - Derek LeRoith
- Division of Endocrinology, Diabetes and Bone Disease, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, USA
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, USA
- Tisch Cancer Institute at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Nina A. Bickell
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, USA
- Tisch Cancer Institute at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Population Health Science and Policy, Center for Health Equity and Community Engaged Research, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Institute for Health Equity Research, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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10
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Biason-Lauber A, Lang-Muritano M. Estrogens: Two nuclear receptors, multiple possibilities. Mol Cell Endocrinol 2022; 554:111710. [PMID: 35787463 DOI: 10.1016/j.mce.2022.111710] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 06/27/2022] [Accepted: 06/28/2022] [Indexed: 11/29/2022]
Abstract
Much is known about estrogen action in experimental animal models and in human physiology. This article reviews the mechanisms of estrogen activity in animals and humans and the role of its two receptors α and β in terms of structure and mechanisms of action in various tissues in health and in relationship with human pathologies (e.g., osteoporosis). Recently, the spectrum of clinical pictures of estrogen resistance caused by estrogen receptors gene variants has been widened by our description of a woman with β-receptor defect, which could be added to the already known descriptions of α-receptor defect in women and men and β-receptor defect in men. The essential role of the β-receptor in the development of the gonad stands out. We summarize the clinical pictures due to estrogen resistance in men and women and focus on long-term follow-up of two women, one with α- and the other with β-receptor resistance. Some open questions remain on the complex interactions between the two receptors on bone metabolism and hypothalamus-pituitary-gonadal axis, which need further deepening and research.
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Affiliation(s)
- Anna Biason-Lauber
- University of Fribourg, Division of Endocrinology, Chemin du Musée 5, 1700, Fribourg, Switzerland.
| | - Mariarosaria Lang-Muritano
- Division of Pediatric Endocrinology and Diabetology, Switzerland; Children's Research Center, University Children's Hospital, Steinwiesstrasse 75, 8032, Zurich, Switzerland
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11
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Scordamaglia D, Cirillo F, Talia M, Santolla MF, Rigiracciolo DC, Muglia L, Zicarelli A, De Rosis S, Giordano F, Miglietta AM, De Francesco EM, Vella V, Belfiore A, Lappano R, Maggiolini M. Metformin counteracts stimulatory effects induced by insulin in primary breast cancer cells. J Transl Med 2022; 20:263. [PMID: 35672854 PMCID: PMC9172136 DOI: 10.1186/s12967-022-03463-y] [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: 04/15/2022] [Accepted: 05/25/2022] [Indexed: 11/13/2022] Open
Abstract
Background Metabolic disorders are associated with increased incidence, aggressive phenotype and poor outcome of breast cancer (BC) patients. For instance, hyperinsulinemia is an independent risk factor for BC and the insulin/insulin receptor (IR) axis is involved in BC growth and metastasis. Of note, the anti-diabetic metformin may be considered in comprehensive therapeutic approaches in BC on the basis of its antiproliferative effects obtained in diverse pre-clinical and clinical studies. Methods Bioinformatics analysis were performed using the information provided by The Invasive Breast Cancer Cohort of The Cancer Genome Atlas (TCGA) project. The naturally immortalized BC cell line, named BCAHC-1, as well as cancer-associated fibroblasts (CAFs) derived from BC patients were used as model systems. In order to identify further mechanisms that characterize the anticancer action of metformin in BC, we performed gene expression and promoter studies as well as western blotting experiments. Moreover, cell cycle analysis, colony and spheroid formation, actin cytoskeleton reorganization, cell migration and matrigel drops evasion assays were carried out to provide novel insights on the anticancer properties of metformin. Results We first assessed that elevated expression and activation of IR correlate with a worse prognostic outcome in estrogen receptor (ER)-positive BC. Thereafter, we established that metformin inhibits the insulin/IR-mediated activation of transduction pathways, gene changes and proliferative responses in BCAHC-1 cells. Then, we found that metformin interferes with the insulin-induced expression of the metastatic gene CXC chemokine receptor 4 (CXCR4), which we found to be associated with poor disease-free survival in BC patients exhibiting high levels of IR. Next, we ascertained that metformin prevents a motile phenotype of BCAHC-1 cells triggered by the paracrine liaison between tumor cells and CAFs upon insulin activated CXCL12/CXCR4 axis. Conclusions Our findings provide novel mechanistic insights regarding the anti-proliferative and anti-migratory effects of metformin in both BC cells and important components of the tumor microenvironment like CAFs. Further investigations are warranted to corroborate the anticancer action of metformin on the tumor mass toward the assessment of more comprehensive strategies halting BC progression, in particular in patients exhibiting metabolic disorders and altered insulin/IR functions. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-022-03463-y.
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12
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Abstract
OBJECTIVE Previous studies on the association between glycaemic index (GI) and glycaemic load (GL) in relation to breast cancer risk are contradictory. The aim of this study was to examine the association between dietary GI and GL and risk of breast cancer in Iranian women. DESIGN Population-based case-control study. Dietary GI and GL were assessed using a validated Willett-format 106-item semi-quantitative FFQ. SETTING Isfahan, Iran. PARTICIPANTS Cases were 350 patients with newly diagnosed stage I-IV breast cancer, for whom the status of breast cancer was confirmed by physical examination and mammography. Controls were 700 age-matched apparently healthy individuals who were randomly selected from general population. RESULTS After controlling for potential confounders, individuals in the highest tertile of dietary GI had 47 % higher odds of breast cancer than women in the lowest tertile (OR: 1·47; (95 % CI 1·02, 2·12)). Stratified analysis by menopausal status showed such association among postmenopausal women (OR: 1·51; (95 % CI 1·02, 2·23)). We found no significant association between dietary GL and odds of breast cancer either before (OR: 1·35; (95 % CI 0·99, 1·84)) or after adjustment for potential confounders (OR: 1·24; (95 % CI 0·86, 1·79)). In addition, stratified analysis by menopausal status revealed no significant association between dietary GL and odds of breast cancer. CONCLUSIONS Our findings showed a significant positive association between dietary GI and odds of breast cancer. However, we observed no significant association between dietary GL and odds of breast cancer.
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13
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Lappano R, Todd LA, Stanic M, Cai Q, Maggiolini M, Marincola F, Pietrobon V. Multifaceted Interplay between Hormones, Growth Factors and Hypoxia in the Tumor Microenvironment. Cancers (Basel) 2022; 14:539. [PMID: 35158804 PMCID: PMC8833523 DOI: 10.3390/cancers14030539] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 01/17/2022] [Accepted: 01/18/2022] [Indexed: 02/07/2023] Open
Abstract
Hormones and growth factors (GFs) are signaling molecules implicated in the regulation of a variety of cellular processes. They play important roles in both healthy and tumor cells, where they function by binding to specific receptors on target cells and activating downstream signaling cascades. The stages of tumor progression are influenced by hormones and GF signaling. Hypoxia, a hallmark of cancer progression, contributes to tumor plasticity and heterogeneity. Most solid tumors contain a hypoxic core due to rapid cellular proliferation that outgrows the blood supply. In these circumstances, hypoxia-inducible factors (HIFs) play a central role in the adaptation of tumor cells to their new environment, dramatically reshaping their transcriptional profile. HIF signaling is modulated by a variety of factors including hormones and GFs, which activate signaling pathways that enhance tumor growth and metastatic potential and impair responses to therapy. In this review, we summarize the role of hormones and GFs during cancer onset and progression with a particular focus on hypoxia and the interplay with HIF proteins. We also discuss how hypoxia influences the efficacy of cancer immunotherapy, considering that a hypoxic environment may act as a determinant of the immune-excluded phenotype and a major hindrance to the success of adoptive cell therapies.
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Affiliation(s)
- Rosamaria Lappano
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy;
| | - Lauren A. Todd
- Department of Biology, University of Waterloo, Waterloo, ON N2L 3G1, Canada;
| | - Mia Stanic
- Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada;
| | - Qi Cai
- Kite Pharma Inc., Santa Monica, CA 90404, USA; (Q.C.); (F.M.)
| | - Marcello Maggiolini
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy;
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14
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Ricci E, Fava M, Rizza P, Pellegrino M, Bonofiglio D, Casaburi I, Lanzino M, Giordano C, Bruno R, Sirianni R, Barone I, Sisci D, Morelli C. FoxO3a Inhibits Tamoxifen-Resistant Breast Cancer Progression by Inducing Integrin α5 Expression. Cancers (Basel) 2022; 14:214. [PMID: 35008379 PMCID: PMC8750403 DOI: 10.3390/cancers14010214] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 12/21/2021] [Accepted: 12/28/2021] [Indexed: 02/05/2023] Open
Abstract
Resistance to endocrine therapy is still a major clinical challenge in the management of estrogen receptor α-positive (ERα+) breast cancer (BC). Here, the role of the Forkhead box class O (FoxO)3a transcription factor in tumor progression has been evaluated in tamoxifen-resistant BC cells (TamR), expressing lower levels of FoxO3a compared to sensitive ones. FoxO3a re-expression reduces TamR motility (wound-healing and transmigration assays) and invasiveness (matrigel transwell invasion assays) through the mRNA (qRT-PCR) and protein (Western blot) induction of the integrin α5 subunit of the α5β1 fibronectin receptor, a well-known membrane heterodimer controlling cell adhesion and signaling. The induction occurs through FoxO3a binding to a specific Forkhead responsive core sequence located on the integrin α5 promoter (cloning, luciferase, and ChIP assays). Moreover, FoxO3a failed to inhibit migration and invasion in integrin α5 silenced (siRNA) cells, demonstrating integrin α5 involvement in both processes. Finally, using large-scale gene expression data sets, a strong positive correlation between FoxO3a and integrin α5 in ERα+, but not in ER-negative (ERα-), BC patients emerged. Altogether, our data show how the oncosuppressor FoxO3a, by increasing the expression of its novel transcriptional target integrin α5, reverts the phenotype of endocrine-resistant BC toward a lower aggressiveness.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | - Diego Sisci
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy; (E.R.); (M.F.); (P.R.); (M.P.); (D.B.); (I.C.); (M.L.); (C.G.); (R.B.); (R.S.); (I.B.)
| | - Catia Morelli
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy; (E.R.); (M.F.); (P.R.); (M.P.); (D.B.); (I.C.); (M.L.); (C.G.); (R.B.); (R.S.); (I.B.)
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15
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Domenici G, Trindade G, Estrada MF, Cartaxo AL, Alves PM, André S, Brito C. Patient-Derived Breast Cancer Tissue Cultures for Anti-Endocrine Drug Assays. Methods Mol Biol 2022; 2535:11-31. [PMID: 35867219 DOI: 10.1007/978-1-0716-2513-2_2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Breast cancer is a complex and heterogeneous pathology, characterized by a variety of histological and molecular phenotypes. The majority of the breast cancers express the estrogen receptor alpha (ER), which plays a pivotal role in the pathobiology of the disease and are therefore classified as ER-positive (ER+). In fact, targeting of the ER signaling pathway is the main therapeutic strategy for ER+ breast cancer. Despite the success of endocrine therapy, intrinsic and acquired resistance are reported in 30-50% of the ER+ breast cancers. However, the mechanisms underlying ER heterogeneity and therapeutic resistance are far from being fully disclosed, and efficacious clinical strategies to overcome resistance are still pending. One of the hurdles in studying ER+ breast cancer resistance is related with the scarcity of experimental models that can recapitulate ER heterogeneity and signaling. This is the case of ER+ breast cancer cell models, typically based on cells derived from metastasis, which also fail to recapitulate tumor complexity. Primary cultures of patient-derived breast cancer cells are difficult to establish, and generally characterized by stromal fibroblasts overgrowth and rapid loss of phenotypic and molecular traits of the tumor cells, including ER expression. Ex vivo cultures of breast cancer tissue have been reported to retain the tissue architecture, with preservation of the tumor microenvironment (TME) and ER expression for short periods of time.Given the cumulating evidence on the role of the TME in sustaining ER+ tumor cells, we hypothesized that TME preservation in culture would favor the long-term retention of ER expression and signaling. We employed alginate encapsulation to provide a supporting scaffold to breast cancer tissue microstructures, coupled to dynamic culture to improve the lifespan of the culture by avoiding diffusional limitations. In this chapter, we provide a detailed description of this culture methodology, which has been previously published by our group (Cartaxo et al., J Exp Clin Cancer Res 39:161, 2020), based on electrostatically driven breast cancer tissue encapsulation in alginate, coupled to culture under agitation in a defined culture medium. We also describe challenge of the ex vivo model with an ER activator and inhibitors (anti-endocrine drugs) and a gene expression endpoint of drug response using reverse transcription PCR-based analysis of three distinct genes downstream of ER.
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Affiliation(s)
- Giacomo Domenici
- iBET, Instituto de Biologia Experimental e Tecnológica, Oeiras, Portugal
- Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Oeiras, Portugal
| | - Gonçalo Trindade
- iBET, Instituto de Biologia Experimental e Tecnológica, Oeiras, Portugal
- Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Oeiras, Portugal
| | - Marta F Estrada
- iBET, Instituto de Biologia Experimental e Tecnológica, Oeiras, Portugal
- Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Oeiras, Portugal
| | - Ana Luísa Cartaxo
- iBET, Instituto de Biologia Experimental e Tecnológica, Oeiras, Portugal
- Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Oeiras, Portugal
| | - Paula M Alves
- iBET, Instituto de Biologia Experimental e Tecnológica, Oeiras, Portugal
- Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Oeiras, Portugal
| | - Saudade André
- IPOLFG, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal
| | - Catarina Brito
- iBET, Instituto de Biologia Experimental e Tecnológica, Oeiras, Portugal.
- Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Oeiras, Portugal.
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16
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Cirillo F, Pellegrino M, Talia M, Perrotta ID, Rigiracciolo DC, Spinelli A, Scordamaglia D, Muglia L, Guzzi R, Miglietta AM, De Francesco EM, Belfiore A, Maggiolini M, Lappano R. Estrogen receptor variant ERα46 and insulin receptor drive in primary breast cancer cells growth effects and interleukin 11 induction prompting the motility of cancer-associated fibroblasts. Clin Transl Med 2021; 11:e516. [PMID: 34841688 PMCID: PMC8567034 DOI: 10.1002/ctm2.516] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 06/21/2021] [Accepted: 07/20/2021] [Indexed: 02/06/2023] Open
Abstract
Among the prognostic and predictive biomarkers of breast cancer (BC), the role of estrogen receptor (ER)α wild-type has been acknowledged, although the action of certain ERα splice variants has not been elucidated. Insulin/insulin receptor (IR) axis has also been involved in the progression and metastasis of BC. For instance, hyperinsulinemia, which is often associated with obesity and type 2 diabetes, may be a risk factor for BC. Similarly, an aberrant expression of IR or its hyperactivation may correlate with aggressive BC phenotypes. In the present study, we have shown that a novel naturally immortalized BC cell line (named BCAHC-1) is characterized by a unique expression of 46 kDa ERα splice variant (ERα46) along with IR. Moreover, we have shown that a multifaceted crosstalk between ERα46 and IR occurs in BCAHC-1 cells upon estrogen and insulin exposure for growth and pulmonary metastasis. Through high-throughput RNA sequencing analysis, we have also found that the cytokine interleukin-11 (IL11) is the main factor linking BCAHC-1 cells to breast cancer-associated fibroblasts (CAFs). In particular, we have found that IL11 induced by estrogens and insulin in BCAHC-1 cells regulates pro-tumorigenic genes of the "extracellular matrix organization" signaling pathway, such as ICAM-1 and ITGA5, and promotes both migratory and invasive features in breast CAFs. Overall, our results may open a new scientific avenue to identify additional prognostic and therapeutic targets in BC.
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Affiliation(s)
- Francesca Cirillo
- Department of PhysicsUniversity of CalabriaRendeItaly
- Department of Pharmacy, Health and Nutritional SciencesUniversity of CalabriaRendeItaly
| | - Michele Pellegrino
- Department of Pharmacy, Health and Nutritional SciencesUniversity of CalabriaRendeItaly
| | - Marianna Talia
- Department of Pharmacy, Health and Nutritional SciencesUniversity of CalabriaRendeItaly
| | - Ida Daniela Perrotta
- Centre for Microscopy and Microanalysis, Transmission Electron Microscopy Laboratory, and Department of Biology, Ecology and Earth SciencesUniversity of CalabriaRendeItaly
| | | | - Asia Spinelli
- Department of Pharmacy, Health and Nutritional SciencesUniversity of CalabriaRendeItaly
| | - Domenica Scordamaglia
- Department of Pharmacy, Health and Nutritional SciencesUniversity of CalabriaRendeItaly
| | - Lucia Muglia
- Department of Pharmacy, Health and Nutritional SciencesUniversity of CalabriaRendeItaly
| | - Rita Guzzi
- Department of PhysicsUniversity of CalabriaRendeItaly
| | | | | | - Antonino Belfiore
- Department of Clinical and Experimental Medicine, University of CataniaGaribaldi‐Nesima HospitalCataniaItaly
| | - Marcello Maggiolini
- Department of Pharmacy, Health and Nutritional SciencesUniversity of CalabriaRendeItaly
| | - Rosamaria Lappano
- Department of Pharmacy, Health and Nutritional SciencesUniversity of CalabriaRendeItaly
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17
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Hanson AM, Kittilson JD, Sheridan MA. Environmental estrogens inhibit the expression of insulin-like growth factor mRNAs in rainbow trout in vitro by altering activation of the JAK-STAT, AKT-PI3K, and ERK signaling pathways. Gen Comp Endocrinol 2021; 309:113792. [PMID: 33872603 DOI: 10.1016/j.ygcen.2021.113792] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Revised: 04/09/2021] [Accepted: 04/13/2021] [Indexed: 11/30/2022]
Abstract
Environmental estrogens (EE) have been found to disrupt a host of developmental, reproductive, metabolic, and osmoregulatory process in a wide-range of animals, particularly those in aquatic ecosystems where such compounds concentrate. Previously, we showed that EE inhibited post-embryonic organismal growth of rainbow trout in vivo, but the precise mechanism(s) through which EE exert their growth inhibiting effects remain unknown. In this study, we used rainbow trout (Oncorhynchus mykiss) as a model to investigate the direct effects of 17β-estradiol (E2), β-sitosterol (βS), and 4-n-nonylphenol (NP) on the synthesis of insulin-like growth factors (IGFs) and to elucidate the mechanism(s) by which EEs exert such effects. E2, βS, and NP significantly inhibited the expression of both IGF-1 and IGF-2 mRNAs in liver and gill in a time- and concentration-related manner. Although the response evoked by each EEs on the expression of IGF mRNAs was similar, the potency and efficacy varied with EE; the rank order potency/efficacy was as follows: E2 > NP > βS. The effects of EEs on the expression of IGF mRNAs was blocked by the estrogen receptor (ER) antagonist, ICI 182780. The mechanism(s) through which EEs inhibit IGF mRNA expression were investigated in isolated liver cells in vitro. EE treatment deactivated JAK, STAT, ERK, and AKT. Moreover, blockade of growth hormone (GH)-stimulated IGF expression by EE was accompanied by deactivation of JAK, STAT, ERK, and AKT. EEs also increased the expression of suppressor of cytokine signaling 2 (SOCS-2), a known inhibitor of JAK-2--an action that also was blocked by ICI 182780. These results indicate that EEs directly inhibit the expression of IGF mRNAs by disrupting GH post-receptor signaling pathways (e.g., JAK, STAT, ERK, and AKT) in an ER-dependent manner.
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Affiliation(s)
- Andrea M Hanson
- Department of Biological Sciences, North Dakota State University, Fargo 58108, USA
| | - Jeffrey D Kittilson
- Department of Biological Sciences, North Dakota State University, Fargo 58108, USA
| | - Mark A Sheridan
- Department of Biological Sciences, North Dakota State University, Fargo 58108, USA.
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18
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Hosseini F, Imani H, Sheikhhossein F, Majdi M, Ghanbari M, Shab-Bidar S. Dietary Carbohydrate Quality and Quantity and Risk of Breast Cancer among Iranian Women. Nutr Cancer 2021; 74:916-926. [PMID: 34180312 DOI: 10.1080/01635581.2021.1942931] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
OBJECTIVE This study investigated the association between quality and quantity of carbohydrate by assessing low carbohydrates diet score (LCDS), carbohydrate quality score (CQI), glycemic index (GI), dietary glycemic load (GL), and dietary carbohydrate intake, and risk of breast cancer (BrCa) among Iranian women. METHODS This hospital-based case-control study was carried out in the Cancer Research Center of Imam Khomeini hospital, Iran. We included One hundred and fifty newly diagnosed BrCa cases and one hundred and fifty healthy controls in this study. Socio-demographic and dietary data and anthropometric measures were recorded. RESULTS We found that a higher CQI than a lower score was associated with a decrease in odds of BrCa (P = 0.04). After adjusting for potential confounders, we observed that CQI was not associated with BrCa development (P = 0.05). An increase in odds of BrCa among women in the highest tertiles of GL (P = 0.12), GI (P = 0.48), and dietary carbohydrate intake (P = 0.06) was seen, which was not statistically significant. There was also a non-significant lower chance of having BrCa with adherence to the LCDS (P = 0.09). CONCLUSION Our findings suggest that CQI was not related to BrCa risk among Iranian women. This relation deserves to be investigated in prospective studies.
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Affiliation(s)
- Fatemeh Hosseini
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Hossein Imani
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Fatemeh Sheikhhossein
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Maryam Majdi
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Mahtab Ghanbari
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Sakineh Shab-Bidar
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, Iran
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19
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Fernandez CJ, George AS, Subrahmanyan NA, Pappachan JM. Epidemiological link between obesity, type 2 diabetes mellitus and cancer. World J Methodol 2021; 11:23-45. [PMID: 34026577 PMCID: PMC8127420 DOI: 10.5662/wjm.v11.i3.23] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 03/02/2021] [Accepted: 03/19/2021] [Indexed: 02/06/2023] Open
Abstract
There exists a complex interaction between obesity, type 2 diabetes mellitus (T2DM) and cancer, and an increase in the incidence of cancer is expected with the growing obesity-diabetes pandemic. The association of cancer with diabetes mellitus and obesity appears to be site-specific, the highest risk being for post-menopausal breast cancer, endometrial cancer, and colorectal cancer. Moreover, there is worsening of hyperglycaemia with the onset of cancer, evidencing a bi-directional link between cancer and diabetes mellitus and the need for monitoring for diabetes in cancer survivors. In this review, we look at the epidemiological evidence from observational studies and Mendelian randomization studies linking obesity, diabetes, and cancer, as well as the complex pathophysiological mechanisms involved, including insulin resistance with associated hyperinsulinaemia, the effect of chronic low-grade inflammation, and the effect of various adipokines that are associated with obesity and T2DM. Additionally, we describe the novel therapeutic strategies, based on their role on the discrete pathophysiological mechanisms involved in the tumourigenesis.
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Affiliation(s)
- Cornelius J Fernandez
- Department of Endocrinology and Metabolism, Pilgrim Hospital, United Lincolnshire Hospitals NHS Trust, Boston PE21 9QS, United Kingdom
| | - Annu Susan George
- Department of Medical Oncology, VPS Lakeshore Hospital, Cochin 682040, India
| | | | - Joseph M Pappachan
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Preston PR2 9HT, United Kingdom
- Faculty of Science, Manchester Metropolitan University, Manchester M15 6BH, United Kingdom
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PL, United Kingdom
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20
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Dong S, Wang Z, Shen K, Chen X. Metabolic Syndrome and Breast Cancer: Prevalence, Treatment Response, and Prognosis. Front Oncol 2021; 11:629666. [PMID: 33842335 PMCID: PMC8027241 DOI: 10.3389/fonc.2021.629666] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Accepted: 03/11/2021] [Indexed: 12/13/2022] Open
Abstract
Metabolic syndrome is a type of multifactorial metabolic disease with the presence of at least three factors: obesity, diabetes mellitus, low high-density lipoprotein, hypertriglyceridemia, and hypertension. Recent studies have shown that metabolic syndrome and its related components exert a significant impact on the initiation, progression, treatment response, and prognosis of breast cancer. Metabolic abnormalities not only increase the disease risk and aggravate tumor progression but also lead to unfavorable treatment responses and more treatment side effects. Moreover, biochemical reactions caused by the imbalance of these metabolic components affect both the host general state and organ-specific tumor microenvironment, resulting in increased rates of recurrence and mortality. Therefore, this review discusses the recent advances in the association of metabolic syndrome and breast cancer, providing potential novel therapeutic targets and intervention strategies to improve breast cancer outcome.
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Affiliation(s)
| | | | - Kunwei Shen
- Department of General Surgery, Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaosong Chen
- Department of General Surgery, Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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21
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Melnik BC. Lifetime Impact of Cow's Milk on Overactivation of mTORC1: From Fetal to Childhood Overgrowth, Acne, Diabetes, Cancers, and Neurodegeneration. Biomolecules 2021; 11:404. [PMID: 33803410 PMCID: PMC8000710 DOI: 10.3390/biom11030404] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 03/04/2021] [Accepted: 03/04/2021] [Indexed: 02/07/2023] Open
Abstract
The consumption of cow's milk is a part of the basic nutritional habits of Western industrialized countries. Recent epidemiological studies associate the intake of cow's milk with an increased risk of diseases, which are associated with overactivated mechanistic target of rapamycin complex 1 (mTORC1) signaling. This review presents current epidemiological and translational evidence linking milk consumption to the regulation of mTORC1, the master-switch for eukaryotic cell growth. Epidemiological studies confirm a correlation between cow's milk consumption and birthweight, body mass index, onset of menarche, linear growth during childhood, acne vulgaris, type 2 diabetes mellitus, prostate cancer, breast cancer, hepatocellular carcinoma, diffuse large B-cell lymphoma, neurodegenerative diseases, and all-cause mortality. Thus, long-term persistent consumption of cow's milk increases the risk of mTORC1-driven diseases of civilization. Milk is a highly conserved, lactation genome-controlled signaling system that functions as a maternal-neonatal relay for optimized species-specific activation of mTORC1, the nexus for regulation of eukaryotic cell growth, and control of autophagy. A deeper understanding of milk´s impact on mTORC1 signaling is of critical importance for the prevention of common diseases of civilization.
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Affiliation(s)
- Bodo C Melnik
- Department of Dermatology, Environmental Medicine and Health Theory, University of Osnabrück, Am Finkenhügel 7a, D-49076 Osnabrück, Germany
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Mukherjee U, Samanta A, Biswas S, Das S, Ghosh S, Mandal DK, Maitra S. Bisphenol A-induced oxidative stress, hepatotoxicity and altered estrogen receptor expression in Labeo bata: impact on metabolic homeostasis and inflammatory response. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2020; 202:110944. [PMID: 32800225 DOI: 10.1016/j.ecoenv.2020.110944] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/25/2020] [Revised: 06/21/2020] [Accepted: 06/22/2020] [Indexed: 05/27/2023]
Abstract
Bisphenol A (BPA), a weak estrogenic endocrine disruptor and a well-known plasticizer, has the potential to perturb diverse physiological functions; however, its impact on immune and metabolic function in aquatic vertebrates is relatively less understood. The present study aims to investigate the impact of BPA on hepatotoxicity, metabolic and immune parameters vis-à-vis estrogen receptor expression modulation in a freshwater teleost, Labeo bata (Cyprinidae, Cypriniformes). The 96-h median lethal concentration of BPA in L. bata has been determined as 4.79 mg/L. Our data demonstrate that congruent with induction of plasma vitellogenin (VTG), chronic exposure to sub-lethal BPA (2 and 4 μM/L) attenuates erythrocyte count, hemoglobin concentration, packed cell volume, mean corpuscular hemoglobin, but not leukocyte number. Further, a significant increase in MDA, concomitant with diminished catalase and heightened GST activity corroborates well with hepatic dystrophic changes, appearance of fatty liver (macrovesicular steatosis) and elevated serum lipids (triglyceride, cholesterol, LDL, VLDL) in BPA-treated groups. Interestingly, a differential regulation of estrogen receptor (ER) subtypes at transcript and protein level signifies negative influence of BPA on hepatic ERα/ERβ homeostasis in this species. While at a lower dose it promotes Akt phosphorylation (activation), BPA at the higher dose attenuates ERK1/2 phosphorylation (activation), suggesting potential alteration in insulin sensitivity. Importantly, dose-dependent decrease in hepatic TNF-α, IL-1β, iNOS (NOS2) expression and nitric oxide (NO) level corresponds well with progressive decline in p-NF-κB, p-p38 MAPK, albeit with differential sensitivity, in BPA-exposed groups. Collectively, BPA exposure has wide-spread negative influence on hematological, biochemical and hepatic events in this species.
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Affiliation(s)
- Urmi Mukherjee
- Department of Zoology, Visva-Bharati University, Santiniketan, 731235, India
| | - Anwesha Samanta
- Department of Zoology, Visva-Bharati University, Santiniketan, 731235, India
| | - Subhasri Biswas
- Department of Zoology, Visva-Bharati University, Santiniketan, 731235, India
| | - Sriparna Das
- Department of Zoology, Visva-Bharati University, Santiniketan, 731235, India
| | - Soumyajyoti Ghosh
- Department of Zoology, Visva-Bharati University, Santiniketan, 731235, India
| | - Dipak Kumar Mandal
- Department of Zoology, Visva-Bharati University, Santiniketan, 731235, India
| | - Sudipta Maitra
- Department of Zoology, Visva-Bharati University, Santiniketan, 731235, India.
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Cartaxo AL, Estrada MF, Domenici G, Roque R, Silva F, Gualda EJ, Loza-Alvarez P, Sflomos G, Brisken C, Alves PM, André S, Brito C. A novel culture method that sustains ERα signaling in human breast cancer tissue microstructures. J Exp Clin Cancer Res 2020; 39:161. [PMID: 32807212 PMCID: PMC7430012 DOI: 10.1186/s13046-020-01653-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Accepted: 07/23/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Estrogen receptor α (ERα) signaling is a defining and driving event in most breast cancers; ERα is detected in malignant epithelial cells of 75% of all breast cancers (classified as ER-positive breast cancer) and, in these cases, ERα targeting is the main therapeutic strategy. However, the biological determinants of ERα heterogeneity and the mechanisms underlying therapeutic resistance are still elusive, hampered by the challenges in developing experimental models recapitulative of intra-tumoral heterogeneity and in which ERα signaling is sustained. Ex vivo cultures of human breast cancer tissue have been proposed to retain the original tissue architecture, epithelial and stromal cell components and ERα. However, loss of cellularity, viability and ERα expression are well-known culture-related phenomena. METHODS BC samples were collected and brought to the laboratory. Then they were minced, enzymatically digested, entrapped in alginate and cultured for 1 month. The histological architecture, cellular composition and cell proliferation of tissue microstructures were assessed by immunohistochemistry. Cell viability was assessed by measurement of cell metabolic activity and histological evaluation. The presence of ERα was accessed by immunohistochemistry and RT-qPCR and its functionality evaluated by challenge with 17-β-estradiol and fulvestrant. RESULTS We describe a strategy based on entrapment of breast cancer tissue microstructures in alginate capsules and their long-term culture under agitation, successfully applied to tissue obtained from 63 breast cancer patients. After 1 month in culture, the architectural features of the encapsulated tissue microstructures were similar to the original patient tumors: epithelial, stromal and endothelial compartments were maintained, with an average of 97% of cell viability compared to day 0. In ERα-positive cases, fibers of collagen, the main extracellular matrix component in vivo, were preserved. ERα expression was at least partially retained at gene and protein levels and response to ERα stimulation and inhibition was observed at the level of downstream targets, demonstrating active ER signaling. CONCLUSIONS The proposed model system is a new methodology to study ex vivo breast cancer biology, in particular ERα signaling. It is suitable for interrogating the long-term effects of anti-endocrine drugs in a set-up that closely resembles the original tumor microenvironment, with potential application in pre- and co-clinical assays of ERα-positive breast cancer.
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Affiliation(s)
- Ana Luísa Cartaxo
- iBET, Instituto de Biologia Experimental e Tecnológica, Oeiras, Portugal
- Instituto de Tecnologia Química e Biológica António Xavier, Oeiras, Portugal
| | - Marta F Estrada
- iBET, Instituto de Biologia Experimental e Tecnológica, Oeiras, Portugal
- Instituto de Tecnologia Química e Biológica António Xavier, Oeiras, Portugal
| | - Giacomo Domenici
- iBET, Instituto de Biologia Experimental e Tecnológica, Oeiras, Portugal
- Instituto de Tecnologia Química e Biológica António Xavier, Oeiras, Portugal
| | - Ruben Roque
- IPOLFG, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal
| | - Fernanda Silva
- CEDOC, Chronic Diseases Research Centre, NOVA Medical School, Universidade NOVA de Lisboa, Lisbon, Portugal
| | - Emilio J Gualda
- ICFO, Institut de Ciències Fotòniques, The Barcelona Institute of Science and Technology, Castelldefels, Barcelona, Spain
| | - Pablo Loza-Alvarez
- ICFO, Institut de Ciències Fotòniques, The Barcelona Institute of Science and Technology, Castelldefels, Barcelona, Spain
| | - George Sflomos
- Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole polytechnique fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Cathrin Brisken
- Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole polytechnique fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Paula M Alves
- iBET, Instituto de Biologia Experimental e Tecnológica, Oeiras, Portugal
- Instituto de Tecnologia Química e Biológica António Xavier, Oeiras, Portugal
| | - Saudade André
- IPOLFG, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal
| | - Catarina Brito
- iBET, Instituto de Biologia Experimental e Tecnológica, Oeiras, Portugal.
- Instituto de Tecnologia Química e Biológica António Xavier, Oeiras, Portugal.
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Andò S, Naimo GD, Gelsomino L, Catalano S, Mauro L. Novel insights into adiponectin action in breast cancer: Evidence of its mechanistic effects mediated by ERα expression. Obes Rev 2020; 21:e13004. [PMID: 32067339 DOI: 10.1111/obr.13004] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Accepted: 01/10/2020] [Indexed: 12/11/2022]
Abstract
This review describes the multifaceted effects of adiponectin on breast cancer cell signalling, tumour metabolism, and microenvironment. It is largely documented that low adiponectin levels are associated with an increased risk of breast cancer. However, it needs to be still clarified what are the extents of the decrease of local/intra-tumoural adiponectin concentrations, which promote breast tumour malignancy. Most of the anti-proliferative and pro-apoptotic effects induced by adiponectin have been obtained in breast cancer cells not expressing estrogen receptor alpha (ERα). Here, we will highlight recent findings demonstrating the mechanistic effects through which adiponectin is able to fuel genomic and non-genomic estrogen signalling, inhibiting LKB1/AMPK/mTOR/S6K pathway and switching energy balance. Therefore, it emerges that the reduced adiponectin levels in patients with obesity work to sustain tumour growth and progression in ERα-positive breast cancer cells. All this may contribute to remove the misleading paradigm that adiponectin univocally inhibits breast cancer cell growth and progression independently on ERα status. The latter concept, here clearly provided by pre-clinical studies, may have translational relevance adopting adiponectin as a potential therapeutic tool. Indeed, the interfering role of ERα on adiponectin action addresses how a separate assessment of adiponectin treatment needs to be considered in novel therapeutic strategies for ERα-positive and ERα-negative breast cancer.
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Affiliation(s)
- Sebastiano Andò
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Italy.,Centro Sanitario, University of Calabria, Arcavacata di Rende, Italy
| | - Giuseppina Daniela Naimo
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Italy
| | - Luca Gelsomino
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Italy
| | - Stefania Catalano
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Italy
| | - Loredana Mauro
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Italy
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Somasundaram A, Rothenberger NJ, Stabile LP. The Impact of Estrogen in the Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1277:33-52. [PMID: 33119863 DOI: 10.1007/978-3-030-50224-9_2] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Tumor immune escape is now a hallmark of cancer development, and therapies targeting these pathways have emerged as standard of care. Specifically, immune checkpoint signal blockade offers durable responses and increased overall survival. However, the majority of cancer patients still do not respond to checkpoint blockade immune therapy leading to an unmet need in tumor immunology research. Sex-based differences have been noted in the use of cancer immunotherapy suggesting that sex hormones such as estrogen may play an important role in tumor immune regulation. Estrogen signaling already has a known role in autoimmunity, and the estrogen receptor can be expressed across multiple immune cell populations and effect their regulation. While it has been well established that tumor cells such as ovarian carcinoma, breast carcinoma, and even lung carcinoma can be regulated by estrogen, research into the role of estrogen in the regulation of tumor-associated immune cells is still emerging. In this chapter, we discuss the role of estrogen in the tumor immune microenvironment and the possible immunotherapeutic implications of targeting estrogen in cancer patients.
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Affiliation(s)
- Ashwin Somasundaram
- Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh, Pittsburgh, PA, USA.,Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA.,UPMC Hillman Cancer Center, Pittsburgh, PA, USA
| | - Natalie J Rothenberger
- Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh, Pittsburgh, PA, USA.,Geisinger Commonwealth School of Medicine, Scranton, PA, USA
| | - Laura P Stabile
- UPMC Hillman Cancer Center, Pittsburgh, PA, USA. .,Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.
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26
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Tang C, Liu P, Zhou Y, Jiang B, Song Y, Sheng L. Sirt6 deletion in hepatocytes increases insulin sensitivity of female mice by enhancing ERα expression. J Cell Physiol 2019; 234:18615-18625. [PMID: 30912134 DOI: 10.1002/jcp.28500] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Revised: 02/22/2019] [Accepted: 03/06/2019] [Indexed: 01/14/2023]
Abstract
Sirtuin 6 (Sirt6), a NAD+ -dependent protein deacetylase, is involved in hepatic glucose metabolism and insulin sensitivity, which impact metabolic homeostasis. In this paper, we discover that Sirt6 affects the insulin sensitivity of mice in a gender-dependent manner; few studies have been conducted on this issue. Based on reports revealing the influences of sex hormones on insulin signaling, this investigation explores the mechanism by which Sirt6 regulates the estrogen pathway and disrupts insulin signal transduction. Hepatocyte-specific Sirt6 knockout (Sirt6HKO) mice were generated to investigate the function of Sirt6 in hepatocytes. Mice were castrated or spayed to eliminate sex hormones. Insulin sensitivity was assessed via an insulin tolerance test (ITT) in vivo. The interaction of Sirt6 with the estrogen pathway and their impacts on insulin signal transduction were revealed by immunoblot and immunoprecipitation. Sirt6 deletion in hepatocytes significantly enhanced insulin sensitivity and signal transduction in female mice but not in male or spayed female mice as demonstrated by ITT and the phosphorylation level of Akt in the liver. We also identified upregulation of p300, ERα, and interaction of ERα with p85 in the liver of female Sirt6HKO mice. Additionally, Sirt6 was found to inhibit ERα protein stability in a p300-dependent manner without interacting directly with ERα. Our findings show that hepatic Sirt6 downregulates the ERα protein level in a p300-dependent manner and thus disturbs estrogen-induced improvement in insulin sensitivity in the liver, which may partially explain the gender difference in insulin sensitivity.
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Affiliation(s)
- Chuanfeng Tang
- Department of Pharmacology, School of Basic Medical Science, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Peiyu Liu
- Department of Pharmacology, School of Basic Medical Science, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yu Zhou
- Department of Pharmacology, School of Basic Medical Science, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Bijie Jiang
- Pharmacy College, Xinxiang Medical University, Xinxiang, Henan, China
| | - Yu Song
- Pharmacy College, Xinxiang Medical University, Xinxiang, Henan, China
| | - Liang Sheng
- Department of Pharmacology, School of Basic Medical Science, Nanjing Medical University, Nanjing, Jiangsu, China.,Pharmacy College, Xinxiang Medical University, Xinxiang, Henan, China.,Key Laboratory of Rare Metabolic Diseases, Nanjing Medical University, Nanjing, Jiangsu, China
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27
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Tian W, Teng F, Gao J, Gao C, Liu G, Zhang Y, Yu S, Zhang W, Wang Y, Xue F. Estrogen and insulin synergistically promote endometrial cancer progression via crosstalk between their receptor signaling pathways. Cancer Biol Med 2019; 16:55-70. [PMID: 31119046 PMCID: PMC6528450 DOI: 10.20892/j.issn.2095-3941.2018.0157] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Objective Despite evidence that estrogens and insulin are involved in the development and progression of many cancers, their synergistic role in endometrial carcinoma (EC) has not been analyzed yet. Methods Here, we investigated how estrogens act synergistically with insulin to promote EC progression. Cell growth in vitro and in vivo, effects of estradiol and insulin on apoptosis and cell cycle distribution, and expression and activation of estrogen receptor (ER), insulin receptor (InsR), and key proteins in the PI3K and MAPK pathways were examined after combined stimulation with estradiol and insulin. Results Compared to EC cells treated with estradiol or insulin alone, those treated with both estradiol and insulin exhibited stronger stimulation. Estradiol significantly induced phosphorylation of InsR-β and IRS-1, whereas insulin significantly induced phosphorylation of ER-α. In addition, treatment with both insulin and estradiol together significantly increased the expression and phosphorylation of Akt, MAPK, and ERK. Notably, InsR-β inhibition had a limited effect on estradiol-dependent proliferation, cell cycle, and apoptosis, whereas ER-α inhibition had a limited insulin-dependent effect, in EC cell lines. Insulin and estradiol individually and synergistically promoted EC xenograft growth in mice. Conclusions Estrogen and insulin play synergistic roles in EC carcinogenesis and progression by activating InsR-β and ER-α, promoting a crosstalk between them, and thereby resulting in the activation of downstream PI3K/Akt and MAPK/ERK signaling pathways.
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Affiliation(s)
| | - Fei Teng
- Department of Gynecology and Obstetrics
| | | | - Chao Gao
- Department of Gynecology and Obstetrics
| | | | | | - Shizhu Yu
- Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Wei Zhang
- Department of Cancer Biology, Comprehensive Cancer Center of Wake Forest Baptist Medical Center, Winston-Salem 27157, NC USA
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Bronsveld HK, De Bruin ML, Wesseling J, Sanders J, Hofland I, Jensen V, Bazelier MT, ter Braak B, de Boer A, Vestergaard P, Schmidt MK. The association of diabetes mellitus and insulin treatment with expression of insulin-related proteins in breast tumors. BMC Cancer 2018; 18:224. [PMID: 29486734 PMCID: PMC6389252 DOI: 10.1186/s12885-018-4072-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Accepted: 01/29/2018] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND The insulin receptor (INSR) and the insulin growth factor 1 receptor (IGF1R) play important roles in the etiology of both diabetes mellitus and breast cancer. We aimed to evaluate the expression of hormone and insulin-related proteins within or related to the PI3K and MAPK pathway in breast tumors of women with or without diabetes mellitus, treated with or without insulin (analogues). METHODS Immunohistochemistry was performed on tumor tissue of 312 women with invasive breast cancer, with or without pre-existing diabetes mellitus, diagnosed in 2000-2010, who were randomly selected from a Danish breast cancer cohort. Women with diabetes were 2:1 frequency matched by year of birth and age at breast cancer diagnosis to those without diabetes. Tumor Microarrays were successfully stained for p-ER, EGFR, p-ERK1/2, p-mTOR, and IGF1R, and scored by a breast pathologist. Associations of expression of these proteins with diabetes, insulin treatment (human insulin and insulin analogues) and other diabetes medication were evaluated by multivariable logistic regression adjusting for menopause and BMI; effect modification by menopausal status, BMI, and ER status was assessed using interactions terms. RESULTS We found no significant differences in expression of any of the proteins in breast tumors of women with (n = 211) and without diabetes (n = 101). Among women with diabetes, insulin use (n = 53) was significantly associated with higher tumor protein expression of IGF1R (OR = 2.36; 95%CI:1.02-5.52; p = 0.04) and p-mTOR (OR = 2.35; 95%CI:1.13-4.88; p = 0.02), especially among women treated with insulin analogues. Menopause seemed to modified the association between insulin and IGF1R expression (p = 0.07); the difference in IGF1R expression was only observed in tumors of premenopausal women (OR = 5.10; 95%CI:1.36-19.14; p = 0.02). We found no associations between other types of diabetes medication, such as metformin, and protein expression of the five proteins evaluated. CONCLUSIONS In our study, breast tumors of women with pre-existing diabetes did not show an altered expression of selected PI3K/MAPK pathway-related proteins. We observed an association between insulin treatment and increased p-mTOR and IGF1R expression of breast tumors, especially in premenopausal women. This observation, if confirmed, might be clinically relevant since the use of IGF1R and mTOR inhibitors are currently investigated in clinical trials.
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Affiliation(s)
- Heleen K. Bronsveld
- Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, Netherlands
- Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht University, Utrecht, Netherlands
| | - Marie L. De Bruin
- Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht University, Utrecht, Netherlands
- Copenhagen Centre for Regulatory Science (CORS), University of Copenhagen, Copenhagen, Denmark
| | - Jelle Wesseling
- Department of Pathology, The Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Joyce Sanders
- Department of Pathology, The Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Ingrid Hofland
- Core Facility Molecular Pathology & Biobanking, The Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Vibeke Jensen
- Department of Pathology, Aarhus University Hospital THG, Aarhus, Denmark
| | - Marloes T. Bazelier
- Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht University, Utrecht, Netherlands
| | - Bas ter Braak
- Division of Toxicology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, Netherlands
| | - Anthonius de Boer
- Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht University, Utrecht, Netherlands
| | - Peter Vestergaard
- Departments of Clinical Medicine and Endocrinology, Aalborg University Hospital, Aalborg, Denmark
| | - Marjanka K. Schmidt
- Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, Netherlands
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The Role of the Estrogen Pathway in the Tumor Microenvironment. Int J Mol Sci 2018; 19:ijms19020611. [PMID: 29463044 PMCID: PMC5855833 DOI: 10.3390/ijms19020611] [Citation(s) in RCA: 134] [Impact Index Per Article: 19.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Revised: 02/13/2018] [Accepted: 02/16/2018] [Indexed: 12/15/2022] Open
Abstract
Estrogen receptors are broadly expressed in many cell types involved in the innate and adaptive immune responses, and differentially regulate the production of cytokines. While both genomic and non-genomic tumor cell promoting mechanisms of estrogen signaling are well characterized in multiple carcinomas including breast, ovarian, and lung, recent investigations have identified a potential immune regulatory role of estrogens in the tumor microenvironment. Tumor immune tolerance is a well-established mediator of oncogenesis, with increasing evidence indicating the importance of the immune response in tumor progression. Immune-based therapies such as antibodies that block checkpoint signals have emerged as exciting therapeutic approaches for cancer treatment, offering durable remissions and prolonged survival. However, only a subset of patients demonstrate clinical response to these agents, prompting efforts to elucidate additional immunosuppressive mechanisms within the tumor microenvironment. Evidence drawn from multiple cancer types, including carcinomas traditionally classified as non-immunogenic, implicate estrogen as a potential mediator of immunosuppression through modulation of protumor responses independent of direct activity on tumor cells. Herein, we review the interplay between estrogen and the tumor microenvironment and the clinical implications of endocrine therapy as a novel treatment strategy within immuno-oncology.
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Polivka J, Altun I, Golubnitschaja O. Pregnancy-associated breast cancer: the risky status quo and new concepts of predictive medicine. EPMA J 2018. [PMID: 29515683 DOI: 10.1007/s13167-018-0129-7] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The paper is motivated by severe concerns regarding currently applied care of the pregnancy-associated breast cancer (PABC) characterised by particularly poor outcomes of the disease. Psychological and ethical aspects play a crucial role in PABC: the highest priority not to damage the foetus significantly complicates any treatment generally, and it is quite usual that patients disclaim undergoing any breast cancer treatment during pregnancy. Although, due to global demographic trends, PABC is far from appearing rarely now, severe societal and economic consequences of the disease are still neglected by currently applied reactive medical approach. These actualities require creating new strategies which should be better adapted to the needs of the society at large by advancing the PABC care based on predictive diagnostic approaches specifically in premenopausal women, innovative screening programmes focused on young female populations, targeted prevention in high-risk groups, and optimised treatment concepts. The article summarises the facts and provides recommendations to advance the field-related research and medical services specifically dedicated to the PABC care.
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Affiliation(s)
- Jiri Polivka
- 1Department of Histology and Embryology, Faculty of Medicine in Plzen, Charles University, Plzen, Czech Republic
- 2Biomedical Centre, Faculty of Medicine in Plzen, Charles University, Plzen, Czech Republic
| | - Irem Altun
- 3CEMBIO, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany
| | - Olga Golubnitschaja
- 4Radiological Clinic, Rheinische Friedrich-Wilhelms-Universität Bonn, Sigmund-Freud-Str 25, 53105 Bonn, Germany
- 5Breast Cancer Research Centre, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany
- 6Centre for Integrated Oncology, Cologne-Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany
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Vella V, Nicolosi ML, Giuliano S, Bellomo M, Belfiore A, Malaguarnera R. PPAR-γ Agonists As Antineoplastic Agents in Cancers with Dysregulated IGF Axis. Front Endocrinol (Lausanne) 2017; 8:31. [PMID: 28275367 PMCID: PMC5319972 DOI: 10.3389/fendo.2017.00031] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2016] [Accepted: 02/06/2017] [Indexed: 12/13/2022] Open
Abstract
It is now widely accepted that insulin resistance and compensatory hyperinsulinemia are associated to increased cancer incidence and mortality. Moreover, cancer development and progression as well as cancer resistance to traditional anticancer therapies are often linked to a deregulation/overactivation of the insulin-like growth factor (IGF) axis, which involves the autocrine/paracrine production of IGFs (IGF-I and IGF-II) and overexpression of their cognate receptors [IGF-I receptor, IGF-insulin receptor (IR), and IR]. Recently, new drugs targeting various IGF axis components have been developed. However, these drugs have several limitations including the occurrence of insulin resistance and compensatory hyperinsulinemia, which, in turn, may affect cancer cell growth and survival. Therefore, new therapeutic approaches are needed. In this regard, the pleiotropic effects of peroxisome proliferator activated receptor (PPAR)-γ agonists may have promising applications in cancer prevention and therapy. Indeed, activation of PPAR-γ by thiazolidinediones (TZDs) or other agonists may inhibit cell growth and proliferation by lowering circulating insulin and affecting key pathways of the Insulin/IGF axis, such as PI3K/mTOR, MAPK, and GSK3-β/Wnt/β-catenin cascades, which regulate cancer cell survival, cell reprogramming, and differentiation. In light of these evidences, TZDs and other PPAR-γ agonists may be exploited as potential preventive and therapeutic agents in tumors addicted to the activation of IGF axis or occurring in hyperinsulinemic patients. Unfortunately, clinical trials using PPAR-γ agonists as antineoplastic agents have reached conflicting results, possibly because they have not selected tumors with overactivated insulin/IGF-I axis or occurring in hyperinsulinemic patients. In conclusion, the use of PPAR-γ agonists in combined therapies of IGF-driven malignancies looks promising but requires future developments.
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Affiliation(s)
- Veronica Vella
- Scienze delle Attività Motorie e Sportive, University Kore, Enna, Italy
| | - Maria Luisa Nicolosi
- Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Stefania Giuliano
- Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Maria Bellomo
- Scienze delle Attività Motorie e Sportive, University Kore, Enna, Italy
| | - Antonino Belfiore
- Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
- *Correspondence: Antonino Belfiore,
| | - Roberta Malaguarnera
- Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
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Malaguarnera R, Vella V, Nicolosi ML, Belfiore A. Insulin Resistance: Any Role in the Changing Epidemiology of Thyroid Cancer? Front Endocrinol (Lausanne) 2017; 8:314. [PMID: 29184536 PMCID: PMC5694441 DOI: 10.3389/fendo.2017.00314] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2017] [Accepted: 10/30/2017] [Indexed: 12/13/2022] Open
Abstract
In the past few decades, the incidence of thyroid cancer (TC), namely of its papillary hystotype (PTC), has shown a steady increase worldwide, which has been attributed at least in part to the increasing diagnosis of early stage tumors. However, some evidence suggests that environmental and lifestyle factors can also play a role. Among the potential risk factors involved in the changing epidemiology of TC, particular attention has been drawn to insulin-resistance and related metabolic disorders, such as obesity, type 2 diabetes, and metabolic syndrome, which have been also rapidly increasing worldwide due to widespread dietary and lifestyle changes. In accordance with this possibility, various epidemiological studies have indeed gathered substantial evidence that insulin resistance-related metabolic disorders might be associated with an increased TC risk either through hyperinsulinemia or by affecting other TC risk factors including iodine deficiency, elevated thyroid stimulating hormone, estrogen-dependent signaling, chronic autoimmune thyroiditis, and others. This review summarizes the current literature evaluating the relationship between metabolic disorders characterized by insulin resistance and the risk for TC as well as the possible underlying mechanisms. The potential implications of such association in TC prevention and therapy are discussed.
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Affiliation(s)
- Roberta Malaguarnera
- Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Veronica Vella
- School of Human and Social Sciences, “Kore” University of Enna, Enna, Italy
- *Correspondence: Veronica Vella, ; Antonino Belfiore,
| | - Maria Luisa Nicolosi
- Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Antonino Belfiore
- Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
- *Correspondence: Veronica Vella, ; Antonino Belfiore,
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Tryfonidis K, Zardavas D, Katzenellenbogen BS, Piccart M. Endocrine treatment in breast cancer: Cure, resistance and beyond. Cancer Treat Rev 2016; 50:68-81. [DOI: 10.1016/j.ctrv.2016.08.008] [Citation(s) in RCA: 82] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Revised: 08/22/2016] [Accepted: 08/29/2016] [Indexed: 10/21/2022]
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Al Naib A, Tucker H, Xie G, Keisler D, Bartol F, Rhoads R, Akers R, Rhoads M. Prepubertal tamoxifen treatment affects development of heifer reproductive tissues and related signaling pathways. J Dairy Sci 2016; 99:5780-5792. [DOI: 10.3168/jds.2015-10679] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2015] [Accepted: 03/02/2016] [Indexed: 11/19/2022]
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Stellato C, Porreca I, Cuomo D, Tarallo R, Nassa G, Ambrosino C. The “busy life” of unliganded estrogen receptors. Proteomics 2015; 16:288-300. [DOI: 10.1002/pmic.201500261] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2015] [Revised: 09/14/2015] [Accepted: 10/15/2015] [Indexed: 12/17/2022]
Affiliation(s)
- Claudia Stellato
- Laboratory of Molecular Medicine and Genomics; Department of Medicine and Surgery; University of Salerno; Baronissi Salerno Italy
| | | | - Danila Cuomo
- Department of Science and Technology; University of Sannio; Benevento Italy
- Biogem scarl; Ariano Irpino (AV); Italy
| | - Roberta Tarallo
- Laboratory of Molecular Medicine and Genomics; Department of Medicine and Surgery; University of Salerno; Baronissi Salerno Italy
| | - Giovanni Nassa
- Laboratory of Molecular Medicine and Genomics; Department of Medicine and Surgery; University of Salerno; Baronissi Salerno Italy
| | - Concetta Ambrosino
- Department of Science and Technology; University of Sannio; Benevento Italy
- Biogem scarl; Ariano Irpino (AV); Italy
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Mauro L, Naimo GD, Ricchio E, Panno ML, Andò S. Cross-Talk between Adiponectin and IGF-IR in Breast Cancer. Front Oncol 2015; 5:157. [PMID: 26236690 PMCID: PMC4502352 DOI: 10.3389/fonc.2015.00157] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Accepted: 06/29/2015] [Indexed: 01/22/2023] Open
Abstract
Obesity is a chronic and multifactorial disorder that is reaching epidemic proportions. It is characterized by an enlarged mass of adipose tissue caused by a combination of size increase of preexisting adipocytes (hypertrophy) and de novo adipocyte differentiation (hyperplasia). Obesity is related to many metabolic disorders like hypertension, type 2 diabetes, metabolic syndrome, and cardiovascular disease, and it is associated with an increased risk of cancer development in different tissues including breast. Adipose tissue is now regarded as not just a storage reservoir for excess energy, but rather as an endocrine organ, secreting a large number of bioactive molecules called adipokines. Among these, adiponectin represents the most abundant adipose tissue-excreted protein, which exhibits insulin sensitizing, anti-inflammatory, and antiatherogenic properties. The serum concentrations of adiponectin are inversely correlated with body mass index. Recently, low levels of plasma adiponectin have been associated with an increased risk for obesity-related cancers and development of more aggressive phenotype, concomitantly with alterations in the bioavailability of insulin-like growth factor-I (IGF-I) and IGF-I receptor (IGF-IR) signaling pathways. In this review, we discuss the cross-talk between adiponectin/AdipoR1 and IGF-I/IGF-IR in breast cancer.
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Affiliation(s)
- Loredana Mauro
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria , Cosenza , Italy
| | - Giuseppina Daniela Naimo
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria , Cosenza , Italy
| | - Emilia Ricchio
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria , Cosenza , Italy
| | - Maria Luisa Panno
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria , Cosenza , Italy
| | - Sebastiano Andò
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria , Cosenza , Italy
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Farvid MS, Eliassen AH, Cho E, Chen WY, Willett WC. Adolescent and Early Adulthood Dietary Carbohydrate Quantity and Quality in Relation to Breast Cancer Risk. Cancer Epidemiol Biomarkers Prev 2015; 24:1111-20. [PMID: 25805068 DOI: 10.1158/1055-9965.epi-14-1401] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2014] [Accepted: 03/14/2015] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND We investigated quantity and quality of dietary carbohydrate as well as insulin load and insulin index during adolescence and also early adulthood in relation to risk of breast cancer in the Nurses' Health Study II. METHODS During 20 years of follow-up of 90,534 premenopausal women who completed a diet questionnaire in 1991, 2,833 invasive breast cancer cases were documented. In 1998, 44,263 of these women also completed a questionnaire about their diet during high school; among these women, we documented 1,118 cases of breast cancer. Multivariable-adjusted Cox proportional hazards regression was used to model relative risks (RR) and 95% confidence intervals (95% CI) for breast cancer across categories of dietary carbohydrate, glycemic index (GI), glycemic load (GL), as well as insulin load and insulin index scores. RESULTS Adolescent or early adult intakes of GI or GL were not associated with risk of breast cancer. Comparing women in the highest versus lowest quintile, the multivariable-adjusted RRs were 1.14 (0.95-1.38) for adolescent GI scores and 1.03 (0.91-1.16) for early adulthood GI scores. We also did not observe associations with insulin index and insulin load scores in adolescence or early adulthood and breast cancer risk. CONCLUSIONS We found that diets high in GI, GL, insulin index, and insulin load during adolescence or early adulthood were not associated with an increased risk of breast cancer in this cohort study. IMPACT Diets with a high glucose or insulin response in adolescence or early adulthood were not significant predictors of breast cancer incidence.
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Affiliation(s)
- Maryam S Farvid
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. Department of Community Nutrition, Faculty of Nutrition Sciences and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - A Heather Eliassen
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Eunyoung Cho
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Department of Dermatology, The Warren Alpert Medical School of Brown University, Providence, Rhode Island
| | - Wendy Y Chen
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Walter C Willett
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
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De Marco P, Cirillo F, Vivacqua A, Malaguarnera R, Belfiore A, Maggiolini M. Novel Aspects Concerning the Functional Cross-Talk between the Insulin/IGF-I System and Estrogen Signaling in Cancer Cells. Front Endocrinol (Lausanne) 2015; 6:30. [PMID: 25798130 PMCID: PMC4351617 DOI: 10.3389/fendo.2015.00030] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2015] [Accepted: 02/19/2015] [Indexed: 12/13/2022] Open
Abstract
The insulin/IGF system plays an important role in cancer progression. Accordingly, elevated levels of circulating insulin have been associated with an increased cancer risk as well as with aggressive and metastatic cancer phenotypes. Numerous studies have documented that estrogens cooperate with the insulin/IGF system in multiple pathophysiological conditions. The biological responses to estrogens are mainly mediated by the estrogen receptors (ER)α and ERβ, which act as transcription factors; however, several studies have recently demonstrated that a member of the G protein-coupled receptors, named GPR30/G-protein estrogen receptor (GPER), is also involved in the estrogen signaling in normal and malignant cells as well as in cancer-associated fibroblasts (CAFs). In this regard, novel mechanisms linking the action of estrogens through GPER with the insulin/IGF system have been recently demonstrated. This review recapitulates the relevant aspects of this functional cross-talk between the insulin/IGF and the estrogenic GPER transduction pathways, which occurs in various cell types and may account for cancer progression.
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Affiliation(s)
- Paola De Marco
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy
| | - Francesca Cirillo
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy
| | - Adele Vivacqua
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy
| | - Roberta Malaguarnera
- Endocrinology, Department of Health, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Antonino Belfiore
- Endocrinology, Department of Health, University Magna Graecia of Catanzaro, Catanzaro, Italy
- *Correspondence: Antonino Belfiore, Università degli Studi Magna Graecia di Catanzaro, Viale Europa, Loc. Germaneto, Catanzaro 88100, Italy e-mail: ; Marcello Maggiolini, Università della Calabria, via P. Bucci, Rende 87036, Italy e-mail:
| | - Marcello Maggiolini
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy
- *Correspondence: Antonino Belfiore, Università degli Studi Magna Graecia di Catanzaro, Viale Europa, Loc. Germaneto, Catanzaro 88100, Italy e-mail: ; Marcello Maggiolini, Università della Calabria, via P. Bucci, Rende 87036, Italy e-mail:
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Lee SC, Tsai SM, Hou MF, Tien LY, Wu SH, Hou LA, Tsai JM, Tsai LY. Increased Igf-I/Igfbp-3 Ratios in Postmenopausal Taiwanese with Breast Cancer, Irrespective of Er and Pr Statuses and Her2 Expression in a Case-Control Study. J Clin Lab Anal 2014; 30:58-64. [PMID: 25385317 DOI: 10.1002/jcla.21815] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2014] [Revised: 07/03/2014] [Accepted: 08/25/2014] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND In most research, there were positive associations between the insulin-like growth factor I (IGF-I) status, including IGF-I, insulin-like growth factor binding protein-3 (IGFBP-3), and ratio of IGF-I/IGFBP-3, and risks of breast cancer (BC), which was influenced by many factors, including hormone statuses and ethnicity. Therefore, the alterations of the IGF-I status in Taiwanese women with BC by menopausal statuses and hormone receptors were investigated. METHODS The levels of IGF-I and IGFBP-3 were determined by the enzyme-labeled chemiluminescent immunometric assay, and the protein expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 (HER2) on paraffin-embedded sections of tissues with BC were analyzed by the immunohistochemical method. RESULTS The ratios of IGF-I/IGFBP-3 were significantly higher in the women with BC than those in the controls, but not of the levels of IGF-I and IGFBP-3; furthermore, the significantly higher ratios were found only in the postmenopausal status. In addition, there was no significant difference between the IGF-I status and ER and PR statuses, and HER2 expression, respectively, in the women with BC. CONCLUSIONS The ratios of IGF-I/IGFBP-3 were increased in postmenopausal Taiwanese women with BC, irrespective of their ages, ER and PR statuses, and HER2 expression.
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Affiliation(s)
- Su-Chen Lee
- Department of Laboratory Medicine, Faculty of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Shih-Meng Tsai
- Department of Public Health and Environmental Medicine, Faculty of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Feng Hou
- Department of Surgery and Faculty of Medicine, Kaohsiung Medical University Hospital and Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Li-Ying Tien
- Division of General Laboratory, Department of Laboratory Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Szu-Hsien Wu
- Division of Plastic Surgery and Department of Surgery, Taipei Veterans General Hospital and Yang Ming University, Taipei, Taiwan
| | - Lisa Ann Hou
- Herman Ostrow School of Dentistry, University of Southern California, Los Angeles, California
| | - Joseph M Tsai
- University of California San Diego, La Jolla, California
| | - Li-Yu Tsai
- Department of Medical Laboratory Science and Biotechnology, College of Health Sciences, Kaohsiung Medical University, Kaohsiung, Taiwan
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De Amicis F, Guido C, Santoro M, Lanzino M, Panza S, Avena P, Panno ML, Perrotta I, Aquila S, Andò S. A novel functional interplay between Progesterone Receptor-B and PTEN, via AKT, modulates autophagy in breast cancer cells. J Cell Mol Med 2014; 18:2252-65. [PMID: 25216078 PMCID: PMC4224558 DOI: 10.1111/jcmm.12363] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2014] [Accepted: 06/02/2014] [Indexed: 12/20/2022] Open
Abstract
The tumour suppressor activity of the phosphatase and tensin homologue on chromosome 10 (PTEN) is subject of intense investigative efforts, although limited information on its regulation in breast cancer is available. Herein, we report that, in breast cancer cells, progesterone (OHPg), through its cognate receptor PR-B, positively modulates PTEN expression by inducing its mRNA and protein levels, and increasing PTEN-promoter activity. The OHPg-dependent up-regulation of PTEN gene activity requires binding of the PR-B to an Sp1-rich region within the PTEN gene promoter. Indeed, ChIP and EMSA analyses showed that OHPg treatment induced the occupancy of PTEN promoter by PR and Sp1 together with transcriptional coactivators such as SRC1 and CBP. PR-B isoform knockdown abolished the complex formation indicating its specific involvement. The OHPg/PR-B dependent induction of PTEN causes the down-regulation of PI3K/AKT signal, switching on the autophagy process through an enhanced expression of UVRAG and leading to a reduced cell survival. Altogether these findings highlight a novel functional connection between OHPg/PR-B and tumour suppressor pathways in breast cancer.
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Affiliation(s)
- Francesca De Amicis
- Centro Sanitario, University of Calabria, Arcavacata di Rende (CS), Italy; Department of Pharmacy, Health Science and Nutrition, University of Calabria, Arcavacata di Rende (CS), Italy
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Panno ML, Giordano F. Effects of psoralens as anti-tumoral agents in breast cancer cells. World J Clin Oncol 2014; 5:348-358. [PMID: 25114850 PMCID: PMC4127606 DOI: 10.5306/wjco.v5.i3.348] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2014] [Revised: 05/14/2014] [Accepted: 06/11/2014] [Indexed: 02/06/2023] Open
Abstract
This review examines the biological properties of coumarins, widely distributed at the highest levels in the fruit, followed by the roots, stems and leaves, by considering their beneficial effects in the prevention of some diseases and as anti-cancer agents. These compounds are well known photosensitizing drugs which have been used as pharmaceuticals for a broad number of therapeutic applications requiring cell division inhibitors. Despite this, even in the absence of ultraviolet rays they are active. The current paper mainly focuses on the effects of psoralens on human breast cancer as they are able to influence many aspects of cell behavior, such as cell growth, survival and apoptosis. In addition, analytical and pharmacological data have demonstrated that psoralens antagonize some metabolizing enzymes, affect estrogen receptor stability and counteract cell invasiveness as well as cancer drug resistance. The scientific findings summarized highlight the pleiotropic functions of phytochemical drugs, given that recently their target signals and how these are modified in the cells have been identified. The encouraging results in this field suggest that multiple modulating strategies based on coumarin drugs in combination with canonical chemotherapeutic agents or radiotherapy could be a useful approach to address the treatment of many types of cancer.
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Liu Y, Hu Z. Identification of collaborative driver pathways in breast cancer. BMC Genomics 2014; 15:605. [PMID: 25034939 PMCID: PMC4111852 DOI: 10.1186/1471-2164-15-605] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2014] [Accepted: 07/07/2014] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND An important challenge in cancer biology is to computationally screen mutations in cancer cells, separating those that might drive cancer initiation and progression, from the much larger number of bystanders. Since mutations are large in number and diverse in type, the frequency of any particular mutation pattern across a set of samples is low. This makes statistical distinctions and reproducibility across different populations difficult to establish. RESULTS In this paper we develop a novel method that promises to partially ameliorate these problems. The basic idea is although mutations are highly heterogeneous and vary from one sample to another, the processes that are disrupted when cells undergo transformation tend to be invariant across a population for a particular cancer or cancer subtype. Specifically, we focus on finding mutated pathway-groups that are invariant across samples of breast cancer subtypes. The identification of informative pathway-groups consists of two steps. The first is identification of pathways significantly enriched in genes containing non-synonymous mutations; the second uses pathways so identified to find groups that are functionally related in the largest number of samples. An application to 4 subtypes of breast cancer identified pathway-groups that can highly explicate a particular subtype and rich in processes associated with transformation. CONCLUSIONS In contrast to previous methods that identify pathways across a set of samples without any further validation, we show that mutated pathway-groups can be found in each breast cancer subtype and that such groups are invariant across the majority of samples. The algorithm is available at http://www.visantnet.org/misi/MUDPAC.zip.
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Affiliation(s)
- Yang Liu
- Bioinformatics Graduate Program and Department of Biomedical Engineering, Boston University, 24 Cummington Mall, Boston, MA 02215 USA
| | - Zhenjun Hu
- Bioinformatics Graduate Program and Department of Biomedical Engineering, Boston University, 24 Cummington Mall, Boston, MA 02215 USA
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Tseng CH, Tseng FH. Diabetes and gastric cancer: the potential links. World J Gastroenterol 2014; 20:1701-1711. [PMID: 24587649 PMCID: PMC3930970 DOI: 10.3748/wjg.v20.i7.1701] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2013] [Revised: 11/18/2013] [Accepted: 12/05/2013] [Indexed: 02/06/2023] Open
Abstract
This article reviews the epidemiological evidence linking diabetes and gastric cancer and discusses some of the potential mechanisms, confounders and biases in the evaluation of such an association. Findings from four meta-analyses published from 2011 to 2013 suggest a positive link, which may be more remarkable in females and in the Asian populations. Putative mechanisms may involve shared risk factors, hyperglycemia, Helicobacter pylori (H. pylori) infection, high salt intake, medications and comorbidities. Diabetes may increase the risk of gastric cancer through shared risk factors including obesity, insulin resistance, hyperinsulinemia and smoking. Hyperglycemia, even before the clinical diagnosis of diabetes, may predict gastric cancer in some epidemiological studies, which is supported by in vitro, and in vivo studies. Patients with diabetes may also have a higher risk of gastric cancer through the higher infection rate, lower eradication rate and higher reinfection rate of H. pylori. High salt intake can act synergistically with H. pylori infection in the induction of gastric cancer. Whether a higher risk of gastric cancer in patients with diabetes may be ascribed to a higher intake of salt due to the loss of taste sensation awaits further investigation. The use of medications such as insulin, metformin, sulfonylureas, aspirin, statins and antibiotics may also influence the risk of gastric cancer, but most of them have not been extensively studied. Comorbidities may affect the development of gastric cancer through the use of medications and changes in lifestyle, dietary intake, and the metabolism of drugs. Finally, a potential detection bias related to gastrointestinal symptoms more commonly seen in patients with diabetes and with multiple comorbidities should be pointed out. Taking into account the inconsistent findings and the potential confounders and detection bias in previous epidemiological studies, it is expected that there are still more to be explored for the clarification of the association between diabetes and gastric cancer.
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Mauro L, Pellegrino M, De Amicis F, Ricchio E, Giordano F, Rizza P, Catalano S, Bonofiglio D, Sisci D, Panno ML, Andò S. Evidences that estrogen receptor α interferes with adiponectin effects on breast cancer cell growth. Cell Cycle 2013; 13:553-64. [PMID: 24335340 DOI: 10.4161/cc.27455] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Adiponectin, the most abundant protein secreted by adipose tissue, exhibits insulin-sensitizing, anti-inflammatory, antiatherogenic, and antiproliferative properties. In addition, it appears to play an important role also in the development and progression of several obesity-related malignancies, including breast cancer. Here, we demonstrated that adiponectin induces a dichotomic effect on breast cancer growth. Indeed, it stimulates growth in ERα+ MCF-7 cells while inhibiting proliferation of ERα- MDA-MB-231 cells. Notably, only in MCF-7 cells adiponectin exposure exerts a rapid activation of MAPK phosphorylation, which is markedly reduced when knockdown of the ERα gene occurred. In addition, adiponectin induces rapid IGF-IR phosphorylation in MCF-7 cells, and the use of ERα siRNA prevents this effect. Moreover, MAPK activation induced by adiponectin was reversed by IGF-IR siRNA. Coimmunoprecipitation studies show the existence of a multiprotein complex involving AdipoR1, APPL1, ERα, IGF-IR, and c-Src that is responsible for MAPK signaling activation in ERα+ positive breast cancer cells. It is well known that in addition to the rapid effects through non-genomic mechanisms, ERα also mediates nuclear genomic actions. In this concern, we demonstrated that adiponectin is able to transactivate ERα in MCF-7 cells. We showed the classical features of ERα transactivation: nuclear localization, downregulation of mRNA and protein levels, and upregulation of estrogen-dependent genes. Thus, our study clarifies the molecular mechanism through which adiponectin modulates breast cancer cell growth, providing evidences on the cell-type dependency of adiponectin action in relationship to ERα status.
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Affiliation(s)
- Loredana Mauro
- Department of Pharmacy, Health, and Nutritional Sciences; University of Calabria; Cosenza, Italy
| | - Michele Pellegrino
- Department of Pharmacy, Health, and Nutritional Sciences; University of Calabria; Cosenza, Italy
| | - Francesca De Amicis
- Department of Pharmacy, Health, and Nutritional Sciences; University of Calabria; Cosenza, Italy; Centro Sanitario; University of Calabria; Cosenza, Italy
| | - Emilia Ricchio
- Department of Pharmacy, Health, and Nutritional Sciences; University of Calabria; Cosenza, Italy
| | - Francesca Giordano
- Department of Pharmacy, Health, and Nutritional Sciences; University of Calabria; Cosenza, Italy
| | - Pietro Rizza
- Department of Pharmacy, Health, and Nutritional Sciences; University of Calabria; Cosenza, Italy
| | - Stefania Catalano
- Department of Pharmacy, Health, and Nutritional Sciences; University of Calabria; Cosenza, Italy; Centro Sanitario; University of Calabria; Cosenza, Italy
| | - Daniela Bonofiglio
- Department of Pharmacy, Health, and Nutritional Sciences; University of Calabria; Cosenza, Italy; Centro Sanitario; University of Calabria; Cosenza, Italy
| | - Diego Sisci
- Department of Pharmacy, Health, and Nutritional Sciences; University of Calabria; Cosenza, Italy; Centro Sanitario; University of Calabria; Cosenza, Italy
| | - Maria Luisa Panno
- Department of Pharmacy, Health, and Nutritional Sciences; University of Calabria; Cosenza, Italy
| | - Sebastiano Andò
- Department of Pharmacy, Health, and Nutritional Sciences; University of Calabria; Cosenza, Italy; Centro Sanitario; University of Calabria; Cosenza, Italy
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Woo HD, Park KS, Shin A, Ro J, Kim J. Glycemic Index and Glycemic Load Dietary Patterns and the Associated Risk of Breast Cancer: A Case-control Study. Asian Pac J Cancer Prev 2013; 14:5193-8. [DOI: 10.7314/apjcp.2013.14.9.5193] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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Skandalis SS, Afratis N, Smirlaki G, Nikitovic D, Theocharis AD, Tzanakakis GN, Karamanos NK. Cross-talk between estradiol receptor and EGFR/IGF-IR signaling pathways in estrogen-responsive breast cancers: focus on the role and impact of proteoglycans. Matrix Biol 2013; 35:182-93. [PMID: 24063949 DOI: 10.1016/j.matbio.2013.09.002] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2013] [Revised: 09/13/2013] [Accepted: 09/13/2013] [Indexed: 02/07/2023]
Abstract
In hormone-dependent breast cancer, estrogen receptors are the principal signaling molecules that regulate several cell functions either by the genomic pathway acting directly as transcription factors in the nucleus or by the non-genomic pathway interacting with other receptors and their adjacent pathways like EGFR/IGFR. It is well established in literature that EGFR and IGFR signaling pathways promote cell proliferation and differentiation. Moreover, recent data indicate the cross-talk between ERs and EGFR/IGFR signaling pathways causing a transformation of cell functions as well as deregulation on normal expression pattern of matrix molecules. Specifically, proteoglycans, a major category of extracellular matrix (ECM) and cell surface macromolecules, are modified during malignancy and cause alterations in cancer cell signaling, affecting eventually functional cell properties such as proliferation, adhesion and migration. The on-going strategies to block only one of the above signaling effectors result cancer cells to overcome such inactivation using alternative signaling pathways. In this article, we therefore review the underlying mechanisms in respect to the role of ERs and the involvement of cross-talk between ERs, IGFR and EGFR in breast cancer cell properties and expression of extracellular secreted and cell bound proteoglycans involved in cancer progression. Understanding such signaling pathways may help to establish new potential pharmacological targets in terms of using ECM molecules to design novel anticancer therapies.
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Affiliation(s)
- Spyros S Skandalis
- Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras 26110, Greece
| | - Nikolaos Afratis
- Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras 26110, Greece
| | - Gianna Smirlaki
- Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras 26110, Greece
| | - Dragana Nikitovic
- Department of Anatomy-Histology-Embryology, Medical School, University of Crete, Heraklion 71003, Greece
| | - Achilleas D Theocharis
- Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras 26110, Greece
| | - George N Tzanakakis
- Department of Anatomy-Histology-Embryology, Medical School, University of Crete, Heraklion 71003, Greece
| | - Nikos K Karamanos
- Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras 26110, Greece.
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Sisci D, Maris P, Cesario MG, Anselmo W, Coroniti R, Trombino GE, Romeo F, Ferraro A, Lanzino M, Aquila S, Maggiolini M, Mauro L, Morelli C, Andò S. The estrogen receptor α is the key regulator of the bifunctional role of FoxO3a transcription factor in breast cancer motility and invasiveness. Cell Cycle 2013; 12:3405-20. [PMID: 24047697 DOI: 10.4161/cc.26421] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
The role of the Forkhead box class O (FoxO)3a transcription factor in breast cancer migration and invasion is controversial. Here we show that FoxO3a overexpression decreases motility, invasiveness, and anchorage-independent growth in estrogen receptor α-positive (ERα+) cancer cells while eliciting opposite effects in ERα-silenced cells and in ERα-negative (ERα-) cell lines, demonstrating that the nuclear receptor represents a crucial switch in FoxO3a control of breast cancer cell aggressiveness. In ERα+ cells, FoxO3a-mediated events were paralleled by a significant induction of Caveolin-1 (Cav1), an essential constituent of caveolae negatively associated to tumor invasion and metastasis. Cav1 induction occurs at the transcriptional level through FoxO3a binding to a Forkhead responsive core sequence located at position -305/-299 of the Cav1 promoter. 17β-estradiol (E2) strongly emphasized FoxO3a effects on cell migration and invasion, while ERα and Cav1 silencing were able to reverse them, demonstrating that both proteins are pivotal mediators of these FoxO3a controlled processes. In vivo, an immunohistochemical analysis on tissue sections from patients with ERα+ or ERα- invasive breast cancers or in situ ductal carcinoma showed that nuclear FoxO3a inversely (ERα+) or directly (ERα-) correlated with the invasive phenotype of breast tumors. In conclusion, FoxO3a role in breast cancer motility and invasion depends on ERα status, disclosing a novel aspect of the well-established FoxO3a/ERα interplay. Therefore FoxO3a might become a pursuable target to be suitably exploited in combination therapies either in ERα+ or ERα- breast tumors.
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Affiliation(s)
- Diego Sisci
- Department of Pharmacy and Health and Nutritional Sciences; University of Calabria; Arcavacata di Rende; Cosenza, Italy
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Krishnamoorthy S, Liu Z, Hong A, Zhu R, Chen H, Li T, Zhou X, Gao X. A Novel Phosphopeptide Microarray Based Interactome Map in Breast Cancer Cells Reveals Phosphoprotein-GRB2 Cell Signaling Networks. PLoS One 2013; 8:e67634. [PMID: 23826330 PMCID: PMC3694890 DOI: 10.1371/journal.pone.0067634] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2012] [Accepted: 05/21/2013] [Indexed: 11/23/2022] Open
Abstract
The architecture of cellular proteins connected to form signaling pathways in response to internal and external cues is much more complex than a group of simple protein-protein interactions. Post translational modifications on proteins (e.g., phosphorylation of serine, threonine and tyrosine residues on proteins) initiate many downstream signaling events leading to protein-protein interactions and subsequent activation of signaling cascades leading to cell proliferation, cell differentiation and cell death. As evidenced by a rapidly expanding mass spectrometry database demonstrating protein phosphorylation at specific motifs, there is currently a large gap in understanding the functional significance of phosphoproteins with respect to their specific protein connections in the signaling cascades. A comprehensive map that interconnects phospho-motifs in pathways will enable identification of nodal protein interactions that are sensitive signatures indicating a disease phenotype from the physiological hemostasis and provide clues into control of disease. Using a novel phosphopeptide microarray technology, we have mapped endogenous tyrosine-phosphoproteome interaction networks in breast cancer cells mediated by signaling adaptor protein GRB2, which transduces cellular responses downstream of several RTKs through the Ras-ERK signaling cascade. We have identified several previously reported motif specific interactions and novel interactions. The peptide microarray data indicate that various phospho-motifs on a single protein are differentially regulated in various cell types and shows global downregulation of phosphoprotein interactions specifically in cells with metastatic potential. The study has revealed novel phosphoprotein mediated signaling networks, which warrants further detailed analysis of the nodes of protein-protein interaction to uncover their biomarker or therapeutic potential.
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Affiliation(s)
- Srinivasan Krishnamoorthy
- Department of Biology and Biochemistry, University of Houston, Houston, Texas, United States of America
- * E-mail: (SK); (XG)
| | - Zhonghua Liu
- Department of Biology and Biochemistry, University of Houston, Houston, Texas, United States of America
| | - Ailing Hong
- LC Sciences, Houston, Texas, United States of America
| | - Ruijuan Zhu
- Department of Biology and Biochemistry, University of Houston, Houston, Texas, United States of America
| | - Haosi Chen
- Department of Biology and Biochemistry, University of Houston, Houston, Texas, United States of America
| | - Tongbin Li
- LC Sciences, Houston, Texas, United States of America
| | | | - Xiaolian Gao
- Department of Biology and Biochemistry, University of Houston, Houston, Texas, United States of America
- * E-mail: (SK); (XG)
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Yoon JM, Son KY, Eom CS, Durrance D, Park SM. Pre-existing diabetes mellitus increases the risk of gastric cancer: A meta-analysis. World J Gastroenterol 2013; 19:936-45. [PMID: 23429469 PMCID: PMC3574893 DOI: 10.3748/wjg.v19.i6.936] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2012] [Revised: 10/22/2012] [Accepted: 10/30/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To systematically assess the association between diabetes and incidence of gastric cancer.
METHODS: We searched MedLine (PubMed), EMBASE, and the Cochrane Library without any limitations with respect to publication date or language, we also searched the references of qualifying articles. Case-control studies and cohort studies comparing the risk of gastric cancer between diabetic patients and control subjects were included. We excluded studies reporting only standardized incidence ratios without control groups and those that investigated only mortality but not incidence. Seventeen studies met our criteria, and the qualities of these studies were assessed using the Newcastle-Ottawa Quality Assessment Scale. We performed a meta-analysis of pre-existing diabetes and gastric cancer incidence using the DerSimonian-Laird method for random-effects. For subgroup analyses, we separated the studies by study type, region, sex and method to determine confounding factors and reliability. We also conducted subgroup analyses to examine the effects of smoking, Helicobacter pylori (H. pylori) infection, and cancer site. Publication bias was evaluated using Begg’s test.
RESULTS: A random-effects model meta-analysis showed an increased gastric cancer risk in diabetic patients [relative risk (RR) = 1.19; 95%CI: 1.08-1.31]. Subgroup analyses indicated that this result persisted in cohort studies (RR = 1.20; 95%CI: 1.08-1.34), in studies on populations of both Western (RR = 1.18; 95%CI: 1.03-1.36) and Eastern countries (RR = 1.19; 95%CI: 1.02-1.38), in a female subgroup (RR=1.24; 95%CI: 1.01-1.52), and in highly qualified studies (RR = 1.17; 95%CI: 1.05-1.31). Moreover, these results persisted when the analysis was confined to studies adjusted for well-known gastric cancer risk factors such as smoking (RR = 1.17; 95%CI: 1.01-1.34) and H. pylori infection (RR = 2.35; 95%CI: 1.24-4.46).
CONCLUSION: Pre-existing diabetes mellitus may increase the risk of gastric cancer by approximately 19%. This effect seems to be unrelated to geographical region.
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Aquila S, Santoro M, De Amicis F, Guido C, Bonofiglio D, Lanzino M, Cesario MG, Perrotta I, Sisci D, Morelli C. Red wine consumption may affect sperm biology: The effects of different concentrations of the phytoestrogen Myricetin on human male gamete function. Mol Reprod Dev 2013; 80:155-65. [DOI: 10.1002/mrd.22145] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2012] [Accepted: 12/14/2012] [Indexed: 12/27/2022]
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