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Ge Y, Zhan Z, Ye M, Jin X. The crosstalk between ubiquitination and endocrine therapy. J Mol Med (Berl) 2023; 101:461-486. [PMID: 36961537 DOI: 10.1007/s00109-023-02300-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 02/23/2023] [Accepted: 02/26/2023] [Indexed: 03/25/2023]
Abstract
Endocrine therapy (ET), also known as hormone therapy, refers to the treatment of tumors by regulating and changing the endocrine environment and hormone levels. Its related mechanism is mainly through reducing hormone levels and blocking the binding of hormones to corresponding receptors, thus blocking the signal transduction pathway to stimulate tumor growth. However, with the application of ET, some patients show resistance to ET, which is attributed to abnormal accumulation of hormone receptors (HRs) and the production of multiple mutants of HRs. The targeted degradation of abnormal accumulation protein mediated by ubiquitination is an important approach that regulates the protein level and function of intracellular proteins in eukaryotes. Here, we provide a brief description of the traditional and novel drugs available for ET in this review. Then, we introduce the link between ubiquitination and ET. In the end, we elaborate the clinical application of ET combined with ubiquitination-related molecules. KEY MESSAGES: • A brief description of the traditional and novel drugs available for endocrine therapy (ET). • The link between ubiquitination and ET. • The clinical application of ET combined with ubiquitination-related molecules.
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Affiliation(s)
- Yidong Ge
- The Department of Medical Oncology, The First Hospital of Ningbo University, Ningbo University, Ningbo, 315010, China
- Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Health Science Center, Medical School of Ningbo University, Ningbo University, Ningbo, Zhejiang, 315211, China
| | - Ziqing Zhan
- The Department of Medical Oncology, The First Hospital of Ningbo University, Ningbo University, Ningbo, 315010, China
- Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Health Science Center, Medical School of Ningbo University, Ningbo University, Ningbo, Zhejiang, 315211, China
| | - Meng Ye
- The Department of Medical Oncology, The First Hospital of Ningbo University, Ningbo University, Ningbo, 315010, China.
- Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Health Science Center, Medical School of Ningbo University, Ningbo University, Ningbo, Zhejiang, 315211, China.
| | - Xiaofeng Jin
- The Department of Medical Oncology, The First Hospital of Ningbo University, Ningbo University, Ningbo, 315010, China.
- Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Health Science Center, Medical School of Ningbo University, Ningbo University, Ningbo, Zhejiang, 315211, China.
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Fleming L, Agnew S, Peddie N, Crawford M, Dixon D, MacPherson I. The impact of medication side effects on adherence and persistence to hormone therapy in breast cancer survivors: A quantitative systematic review. Breast 2022; 64:63-84. [PMID: 35609380 PMCID: PMC9130570 DOI: 10.1016/j.breast.2022.04.010] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 04/26/2022] [Accepted: 04/27/2022] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND Hormone Therapy (HT) is recommended for most women with HR-positive primary breast cancer. When taken as intended, HT reduces breast cancer recurrence by 40% and mortality by one-third. The recommended duration of treatment ranges from 5 to 10 years depending on risk of recurrence and the specific HT regimen. However, recent data indicates that rates of HT non-adherence are high and research suggests this may be due to the impact of HT side effects. The contribution of side effects to non-adherence and non-persistence behaviours has rarely been systematically explored, thereby hindering the implementation of targeted intervention strategies. Our aim is to identify, evaluate and summarise the relationship between HT side effects and patterns of adherence and persistence. METHODS Electronic searches were conducted from inception and were completed by September 2021, utilising Cochrane CENTRAL, Medline, Embase, Web of Science and PsycINFO databases. Searches included a combination of terms related to breast cancer, adherence, hormone therapy and side effects. RESULTS Sixty-two eligible papers were identified and study quality varied by study type. Most observational and cross-sectional studies were rated good quality, whereas most controlled intervention studies were rated fair quality. Three studies were rated poor quality. The most frequently measured side effects were pain, low mood, hot flashes, insomnia, anxiety, fatigue, weight gain, concentration/memory problems. CONCLUSIONS This review identified a lack of consistency in the measurement of adherence and the definition of persistence across studies. The instruments used to measure side effects also varied significantly. This variation and lack of consistency makes it difficult to evaluate and summarise the role of HT side effects in HT adherence and persistence behaviour.
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Affiliation(s)
| | - Sommer Agnew
- University of Strathclyde, George Street, Glasgow, UK
| | - Nicola Peddie
- University of Strathclyde, George Street, Glasgow, UK
| | | | - Diane Dixon
- University of Aberdeen, Kings College, Aberdeen, UK
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Printz C. Some patients with postmenopausal breast cancer can avoid adjuvant chemotherapy: Data indicate that some postmenopausal women with breast cancer can safely skip adjuvant chemotherapy. Cancer 2021; 127:1951-1952. [PMID: 34029389 DOI: 10.1002/cncr.33635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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Xi Y, Liu J, Wang H, Li S, Yi Y, Du Y. New small-molecule compound Hu-17 inhibits estrogen biosynthesis by aromatase in human ovarian granulosa cancer cells. Cancer Med 2020; 9:9081-9095. [PMID: 33002342 PMCID: PMC7724309 DOI: 10.1002/cam4.3492] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 07/17/2020] [Accepted: 09/08/2020] [Indexed: 12/20/2022] Open
Abstract
Estrogen-dependent cancers (breast, endometrial, and ovarian) are among the leading causes of morbidity and mortality in women worldwide. Aromatase is the main enzyme that catalyzes the biosynthesis of estrogen, which drives proliferation, and antiestrogens can inhibit the growth of these estrogen-dependent cancers. Hu-17, an aromatase inhibitor, is a novel small-molecule compound that suppresses viability of and promotes apoptosis in ovarian cancer cells. Therefore, this study aimed to predict targets of Hu-17 and assess its intracellular signaling in ovarian cancer cells. Using the Similarity Ensemble Approach software to predict the potential mechanism of Hu-17 and combining phospho-proteome arrays with western blot analysis, we observed that Hu-17 could inhibit the ERK pathway, resulting in reduced estrogen synthesis in KGN cells, a cell line derived from a patient with invasive ovarian granulosa cell carcinoma. Hu-17 reduced the expression of CYP19A1 mRNA, responsible for producing aromatase, by suppressing the phosphorylation of cAMP response element binding-1. Hu-17 also accelerated aromatase protein degradation but had no effect on aromatase activity. Therefore, Hu-17 could serve as a potential treatment for estrogen-dependent cancers albeit further investigation is warranted.
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Affiliation(s)
- Yang Xi
- Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, China.,Central Laboratory, Shanghai Xuhui Central Hospital, Zhongshan-Xuhui Hospital, Fudan University, Shanghai, China
| | - Jiansheng Liu
- Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, China
| | - Haiwei Wang
- Institute of Health Sciences, School of Medicine (SJTUSM)/Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai Jiao Tong University, Shanghai, China
| | - Shang Li
- Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, China
| | - Yanghua Yi
- Research Center for Marine Drugs, School of Pharmacy, Second Military Medical University, Shanghai, China
| | - Yanzhi Du
- Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, China
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Yang V, Gouveia MJ, Santos J, Koksch B, Amorim I, Gärtner F, Vale N. Breast cancer: insights in disease and influence of drug methotrexate. RSC Med Chem 2020; 11:646-664. [PMID: 33479665 PMCID: PMC7578709 DOI: 10.1039/d0md00051e] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Accepted: 05/06/2020] [Indexed: 12/12/2022] Open
Abstract
According to the World Health Organization, cancer is one of the leading causes of morbidity and mortality worldwide. The previously estimated 14 million new cases in the year of 2012 are expected to rise, yearly, over the following 2 decades. Among women, breast cancer is the most common one. In 2012, almost 1.7 million people were diagnosed worldwide and half a million died from the disease. Despite having several treatments available, from surgery to chemotherapy, most of these treatments have severe adverse effects. Chemotherapy has a narrow therapeutic window and requires high dosage treatment in patients with advanced-stage cancers and further need innovative treatment strategies. Although methotrexate (MTX) is not a first line drug used against breast cancer, however, it might be valuable to fight the disease. MTX is an effective and cheap drug that might impair malignant growth without irreversible damage to normal tissues. Nevertheless, while MTX does present some disadvantages including poor solubility and low permeability, several strategies are being used to discover and provide novel and effective targeted treatment against breast cancer. In this review, we analyze the chemotherapy of breast cancer and its relationship with drug MTX.
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Affiliation(s)
- Vítor Yang
- Department of Molecular Pathology and Immunology , Abel Salazar Biomedical Sciences Institute (ICBAS) , University of Porto , Rua de Jorge Viterbo Ferreira, 228 , 4050-313 Porto , Portugal .
- Instituto de Investigação e Inovação em Saúde (i3S) , University of Porto , Rua Alfredo Allen, 208 , 4200-135 Porto , Portugal
| | - Maria João Gouveia
- Department of Molecular Pathology and Immunology , Abel Salazar Biomedical Sciences Institute (ICBAS) , University of Porto , Rua de Jorge Viterbo Ferreira, 228 , 4050-313 Porto , Portugal .
- Instituto de Investigação e Inovação em Saúde (i3S) , University of Porto , Rua Alfredo Allen, 208 , 4200-135 Porto , Portugal
| | - Joana Santos
- Instituto de Investigação e Inovação em Saúde (i3S) , University of Porto , Rua Alfredo Allen, 208 , 4200-135 Porto , Portugal
| | - Beate Koksch
- Department of Chemistry and Biochemistry , Freie Universität Berlin , Takustrasse 3 , 14195 Berlin , Germany
| | - Irina Amorim
- Department of Molecular Pathology and Immunology , Abel Salazar Biomedical Sciences Institute (ICBAS) , University of Porto , Rua de Jorge Viterbo Ferreira, 228 , 4050-313 Porto , Portugal .
- Instituto de Investigação e Inovação em Saúde (i3S) , University of Porto , Rua Alfredo Allen, 208 , 4200-135 Porto , Portugal
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) , Rua Júlio Amaral de Carvalho, 45 , 4200-135 Porto , Portugal
| | - Fátima Gärtner
- Department of Molecular Pathology and Immunology , Abel Salazar Biomedical Sciences Institute (ICBAS) , University of Porto , Rua de Jorge Viterbo Ferreira, 228 , 4050-313 Porto , Portugal .
- Instituto de Investigação e Inovação em Saúde (i3S) , University of Porto , Rua Alfredo Allen, 208 , 4200-135 Porto , Portugal
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) , Rua Júlio Amaral de Carvalho, 45 , 4200-135 Porto , Portugal
| | - Nuno Vale
- Department of Molecular Pathology and Immunology , Abel Salazar Biomedical Sciences Institute (ICBAS) , University of Porto , Rua de Jorge Viterbo Ferreira, 228 , 4050-313 Porto , Portugal .
- Instituto de Investigação e Inovação em Saúde (i3S) , University of Porto , Rua Alfredo Allen, 208 , 4200-135 Porto , Portugal
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) , Rua Júlio Amaral de Carvalho, 45 , 4200-135 Porto , Portugal
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Lee M, Piao J, Jeon MJ. Risk Factors Associated with Endometrial Pathology in Premenopausal Breast Cancer Patients Treated with Tamoxifen. Yonsei Med J 2020; 61:317-322. [PMID: 32233174 PMCID: PMC7105402 DOI: 10.3349/ymj.2020.61.4.317] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 02/11/2020] [Accepted: 02/27/2020] [Indexed: 11/27/2022] Open
Abstract
PURPOSE To evaluate factors associated with endometrial pathology during tamoxifen use in premenopausal breast cancer (BC) patients. MATERIALS AND METHODS We reviewed the medical records of premenopausal BC patients treated with tamoxifen who underwent endometrial biopsy with or without hysteroscopy. Clinical characteristics were compared between women with endometrial pathology (endometrial hyperplasia or cancer) and those with normal histology or endometrial polyps. RESULTS Among 284 endometrial biopsies, endometrial hyperplasia was diagnosed in 7 patients (2.5%), endometrial cancer was diagnosed in 5 patients (1.8%), normal histology was noted in 146 patients (51.4%), and endometrial polyp was present in 114 patients (40.1%). When comparing women with endometrial cancer (n=5) to women with normal histology, abnormal uterine bleeding was more common (p=0.007), and endometrial thickness was greater (p=0.007) in women with endometrial cancer. Chemotherapy for BC was also more common in patients with endometrial cancer (p=0.037). When comparing women with endometrial polyps and those with endometrial hyperplasia or cancer, the presence of abnormal uterine bleeding was more common in patients with endometrial hyperplasia or cancer (p<0.001); however, tamoxifen duration and endometrial thickness did not differ significantly between the two groups. CONCLUSION In premenopausal BC patients treated with tamoxifen, abnormal uterine bleeding, increased endometrial thickness, and chemotherapy for BC were associated with the occurrence of endometrial cancer. These findings may provide useful information for gynecologic surveillance and counseling during tamoxifen treatment in premenopausal BC patients.
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Affiliation(s)
- Maria Lee
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Korea
- Department of Obstetrics and Gynecology, Seoul National University Hospital, Seoul, Korea
| | - Jinlan Piao
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Korea
| | - Myung Jae Jeon
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Korea
- Department of Obstetrics and Gynecology, Seoul National University Hospital, Seoul, Korea.
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Bui KT, Willson ML, Goel S, Beith J, Goodwin A, Cochrane Breast Cancer Group. Ovarian suppression for adjuvant treatment of hormone receptor-positive early breast cancer. Cochrane Database Syst Rev 2020; 3:CD013538. [PMID: 32141074 PMCID: PMC7059882 DOI: 10.1002/14651858.cd013538] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND Approximately 80% of breast cancers amongst premenopausal women are hormone receptor-positive. Adjuvant endocrine therapy is an integral component of care for hormone receptor-positive breast cancer and in premenopausal women includes oestrogen receptor blockade with tamoxifen, temporary suppression of ovarian oestrogen synthesis by luteinising hormone releasing hormone (LHRH) agonists, and permanent interruption of ovarian oestrogen synthesis with oophorectomy or radiotherapy. Recent international consensus statements recommend single-agent tamoxifen or aromatase inhibitors with ovarian function suppression (OFS) as the current standard adjuvant endocrine therapy for premenopausal women (often preceded by chemotherapy). This review examined the role of adding OFS to another treatment (i.e. chemotherapy, endocrine therapy, or both) or comparing OFS to no further adjuvant treatment. OBJECTIVES To assess effects of OFS for treatment of premenopausal women with hormone receptor-positive early breast cancer. SEARCH METHODS For this review update, we searched the Specialised Register of the Cochrane Breast Cancer Group, MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 8), the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), and ClinicalTrials.gov on 26 September 2019. We screened the reference lists of related articles, contacted trial authors, and applied no language restrictions. SELECTION CRITERIA We included all randomised trials assessing any method of OFS, that is, oophorectomy, radiation-induced ovarian ablation, or LHRH agonists, as adjuvant treatment for premenopausal women with early-stage breast cancer. We included studies that compared (1) OFS versus observation, (2) OFS + chemotherapy versus chemotherapy, (3) OFS + tamoxifen versus tamoxifen, and (4) OFS + chemotherapy + tamoxifen versus chemotherapy + tamoxifen. DATA COLLECTION AND ANALYSIS Two review authors independently extracted data and assessed risk of bias and certainty of evidence using the GRADE approach. Hazard ratios (HRs) were derived for time-to-event outcomes, and meta-analysis was performed using a fixed-effect model. The primary outcome measures were overall survival (OS) and disease-free survival (DFS). Toxicity, contralateral breast cancer, and second malignancy were represented as risk ratios (RRs), and quality of life data were extracted when provided. MAIN RESULTS This review update included 15 studies involving 11,538 premenopausal women with hormone receptor-positive early breast cancer; these studies were conducted from 1978 to 2014. Some of these treatments are not current standard of care, and early studies did not assess HER2 receptor status. Studies tested OFS versus observation (one study), OFS plus chemotherapy versus chemotherapy (six studies), OFS plus tamoxifen versus tamoxifen (six studies), and OFS plus chemotherapy and tamoxifen versus chemotherapy and tamoxifen (two studies). Of those studies that reported the chemotherapy regimen, an estimated 72% of women received an anthracycline. The results described below relate to the overall comparison of OFS versus no OFS. High-certainty evidence shows that adding OFS to treatment resulted in a reduction in mortality (hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.78 to 0.94; 11 studies; 10,374 women; 1933 reported events). This treatment effect was seen when OFS was added to observation, to tamoxifen, or to chemotherapy and tamoxifen. The effect on mortality was not observed when OFS was added to chemotherapy without tamoxifen therapy (HR 0.95, 95% CI 0.82 to 1.09; 5 studies; 3087 women; median follow-up: range 7.7 to 12.1 years). The addition of OFS resulted in improved DFS (HR 0.83, 95% CI 0.77 to 0.90; 10 studies; 8899 women; 2757 reported events; high-certainty evidence). The DFS treatment effect persisted when OFS was added to observation, to tamoxifen, and to chemotherapy and tamoxifen. The effect on DFS was reduced when OFS was added to chemotherapy without tamoxifen therapy (HR 0.90, 95% CI 0.79 to 1.01; 5 studies; 2450 women). Heterogeneity was low to moderate across studies for DFS and OS (respectively). Evidence suggests that adding OFS slightly increases the incidence of hot flushes (grade 3/4 or any grade; risk ratio (RR) 1.60, 95% CI 1.41 to 1.82; 6 studies; 5581 women; low-certainty evidence, as this may have been under-reported in these studies). Two other studies that could not be included in the meta-analysis reported a higher number of hot flushes in the OFS group than in the no-OFS group. Seven studies involving 5354 women collected information related to mood; however this information was reported as grade 3 or 4 depression, anxiety, or neuropsychiatric symptoms, or symptoms were reported without the grade. Two studies reported an increase in depression, anxiety, and neuropsychiatric symptoms in the OFS group compared to the no-OFS group, and five studies indicated an increase in anxiety in both treatment groups (but no difference between groups) or no difference overall in symptoms over time or between treatment groups. A single study reported bone health as osteoporosis (defined as T score < -2.5); this limited evidence suggests that OFS increases the risk of osteoporosis compared to no-OFS at median follow-up of 5.6 years (RR 1.16, 95% CI 1.10 to 28.82; 2011 women; low-certainty evidence). Adding OFS to treatment likely reduces the risk of contralateral breast cancer (HR 0.75, 95% CI 0.57 to 0.97; 9 studies; 9138 women; moderate-certainty evidence). Quality of life was assessed in five studies; four studies used validated tools, and the fifth study provided no information on how data were collected. Two studies reported worse quality of life indicators (i.e. vaginal dryness, day and night sweats) for women receiving OFS compared to those in the no-OFS group. The other two studies indicated worsening of symptoms (e.g. vasomotor, gynaecological, vaginal dryness, decline in sexual interest, bone and joint pain, weight gain); however these side effects were reported in both OFS and no-OFS groups. The study that did not use a validated quality of life tool described no considerable differences between groups. AUTHORS' CONCLUSIONS This review found evidence that supports adding OFS for premenopausal women with early, hormone receptor-positive breast cancers. The benefit of OFS persisted when compared to observation, and when added to endocrine therapy (tamoxifen) or chemotherapy and endocrine therapy (tamoxifen). The decision to use OFS may depend on the overall risk assessment based on tumour and patient characteristics, and may follow consideration of all side effects that occur with the addition of OFS.
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Affiliation(s)
- Kim Tam Bui
- Concord Repatriation General HospitalMedical Oncology Department1A Hospital RoadConcordNSWAustralia2137
| | - Melina L Willson
- NHMRC Clinical Trials Centre, The University of SydneySystematic Reviews and Health Technology AssessmentsLocked Bag 77SydneyNSWAustralia1450
| | - Shom Goel
- Peter MacCallum Cancer CentreMelbourneAustralia
- University of MelbourneSir Peter MacCallum Department of OncologyMelbourneAustralia
| | - Jane Beith
- Chris O'Brien LifehouseCamperdownNSWAustralia2050
| | - Annabel Goodwin
- Concord Repatriation General HospitalMedical Oncology Department1A Hospital RoadConcordNSWAustralia2137
- The University of Sydney, Concord Repatriation General HospitalConcord Clinical SchoolConcordNSWAustralia2137
- Sydney Local Health District and South Western Sydney Local Health DistrictCancer Genetics DepartmentSydneyAustralia
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A Potential Anti-Tumor Herb Bred in a Tropical Fruit: Insight into the Chemical Components and Pharmacological Effects of Momordicae Semen. Molecules 2019; 24:molecules24213949. [PMID: 31683690 PMCID: PMC6864475 DOI: 10.3390/molecules24213949] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Revised: 10/25/2019] [Accepted: 10/28/2019] [Indexed: 12/19/2022] Open
Abstract
Gac fruit (Momordica cochinchinensis Spreng) is a popular tropical fruit in southeast Asia. What is amazing is that its seeds (Momordicae Semen) and arils are traditional herbs with anti-tumor activity, and have protected human health for more than 1000 years. In recent years, its anti-tumor activity has received extensive attention and research. This manuscript summarized the chemical composition of saponins, fatty acids, volatile constituents, proteins, peptides, and other components from Momordicae Semen (MSE). The effect and mechanism of MSE and its extract on breast cancer, gastric cancer, lung cancer, esophagus cancer, melanomas, and human cervical epithelial carcinoma were discussed. In addition, its antioxidant, anti-inflammatory, and other pharmacological effects were also analyzed. We hope that this review will provide new ideas for the treatment of cancer and other diseases, and become a reference for the further research into complementary and alternative medicine.
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The effect of tamoxifen therapy on the endometrium and ovarian cyst formation in patients with breast cancer. Obstet Gynecol Sci 2018; 61:615-620. [PMID: 30254998 PMCID: PMC6137019 DOI: 10.5468/ogs.2018.61.5.615] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Revised: 01/12/2018] [Accepted: 01/26/2018] [Indexed: 12/19/2022] Open
Abstract
Objective To evaluate the effect of tamoxifen on female reproductive organs in women with breast cancer. Methods We retrospectively reviewed the medical records of 309 women with breast cancer who were currently receiving tamoxifen and undergoing regular gynecological examination. Results We evaluated 92 pre- and 217 postmenopausal women. The prevalence of endometrial thickening was 12% in the pre- and 10.6% in the postmenopausal group. An endometrial biopsy was performed in 43 women and confirmed endometrial cancer in 1, endometrial polyps in 14, and endometrial hyperplasia in 4 women. Transvaginal ultrasonography showed 25 cases of newly developed ovarian cysts. Most ovarian cysts had disappeared during follow-up. Conclusion Tamoxifen use in women with breast cancer causes few complications and is considered safe for female reproductive organs in case of regular gynecological examination.
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Li XY, Su L, Jiang YM, Gao WB, Xu CW, Zeng CQ, Song J, Xu Y, Weng WC, Liang WB. The Antitumor Effect of Xihuang Pill on Treg Cells Decreased in Tumor Microenvironment of 4T1 Breast Tumor-Bearing Mice by PI3K/AKT~AP-1 Signaling Pathway. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2018; 2018:6714829. [PMID: 29849718 PMCID: PMC5937580 DOI: 10.1155/2018/6714829] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Revised: 02/19/2018] [Accepted: 03/07/2018] [Indexed: 12/20/2022]
Abstract
To study the antitumor effect of Xihuang pill (XHP) on the number of Treg cells in the tumor microenvironment of 4T1 breast tumor-bearing mice by PI3K/AKT/AP-1 pathway, a mouse model was established. Flow cytometry (FCM) and immunohistochemistry (IHC) were used to detect the number of Treg cells in the tumor microenvironment; terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) was used to detect the apoptosis of Treg cells in tumor microenvironment. Quantitative real-time PCR (RT-qPCR) was used to detect the mRNA expression of PI3K, AKT, and AP-1 in Treg cells in tumor microenvironment; immunofluorescence (IF) and Western Blot (WB) were used to detect the protein expression of PI3K, AKT, and AP-1 in Treg cells in tumor microenvironment. Compared with the naive control group, the tumor weight in XHP groups decreased significantly (P < 0.05); FCM and IHC results showed that the number of Treg cells in the tumor microenvironment decreased with the dose of XHP groups (P < 0.05); TUNEL staining showed that the number of Treg cells in tumor microenvironment increased with the dose of XHP groups (P < 0.05); RT-qPCR results showed that the mRNA expression of PI3K and AKT in Treg cells decreased with the dose of XHP groups, while RNA expression of AP-1 increased with the dose of XHP groups (P < 0.05); IF and WB results showed that the protein expression of PI3K and AKT in Treg cells decreased with the dose of XHP groups and the protein expression of AP-1 increased with the dose of XHP groups (P < 0.05). The results suggested that XHP decreased the number of Treg cells via inhibiting PI3K and AKT expression and upregulating AP-1 expression in Treg cells and then promoting the apoptosis of Treg cells. Thus, XHP could improve the immunosuppressive state of tumor microenvironment and reverse the immune escape to inhibit tumor growth.
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Affiliation(s)
- Xin-ye Li
- Medical College of Dalian University, Dalian 116622, China
| | - Liang Su
- Xin Hua Affiliated Hospital of Dalian University, Dalian 116000, China
| | - Yi-ming Jiang
- Xin Hua Affiliated Hospital of Dalian University, Dalian 116000, China
| | - Wen-bin Gao
- Department of Medical Oncology, The 3rd Affiliated Hospital of Shenzhen University, Shenzhen 518001, China
| | - Chun-wei Xu
- Department of Pathology, Affiliated Hospital of Academy of Military Medical Sciences, Beijing 100071, China
| | | | - Jie Song
- Medical College of Dalian University, Dalian 116622, China
| | - Yu Xu
- Medical College of Dalian University, Dalian 116622, China
| | - Wen-cai Weng
- Xin Hua Affiliated Hospital of Dalian University, Dalian 116000, China
| | - Wen-bo Liang
- Medical College of Dalian University, Dalian 116622, China
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Su L, Jiang Y, Xu Y, Li X, Gao W, Xu C, Zeng C, Song J, Weng W, Liang W. Xihuang pill promotes apoptosis of Treg cells in the tumor microenvironment in 4T1 mouse breast cancer by upregulating MEKK1/SEK1/JNK1/AP-1 pathway. Biomed Pharmacother 2018; 102:1111-1119. [PMID: 29710529 DOI: 10.1016/j.biopha.2018.03.063] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2017] [Revised: 03/09/2018] [Accepted: 03/11/2018] [Indexed: 01/14/2023] Open
Abstract
OBJECTIVE To determine the role of the MEKK1/SEK1/JNK1/AP-1 pathway in the action of Xihuang pill (XHP) in reducing regulatory T (Treg) cell numbers in the tumor microenvironment in a 4T1 mouse breast cancer model, and to clarify the anti-tumor mechanism of XHP in breast cancer. METHODS We established a mouse 4T1 breast cancer model. Model mice were administered XHP for 2 weeks, and tumor tissues were then removed, weighed, sliced, and homogenized. Treg cells in the tumor microenvironment were isolated by magnetic cell sorting and analyzed by immunohistochemistry and flow cytometry. Treg cell apoptosis was detected by TdT-mediated dUTP nick end labeling. mRNA expression levels of MEKK1, SEK1, JNK1, and AP-1 in Treg cells in the tumor microenvironment were detected by quantitative real-time PCR and their protein expression levels were detected by immunofluorescence staining and western blot. RESULTS Tumor weights were significantly lower in the XHP groups compared with the untreated control group. The overall number of Treg cells in the tumor microenvironment decreased while the number of apoptotic Treg cells increased with increasing doses of XHP. mRNA and protein expression levels of MEKK1, SEK1, JNK1, and AP-1 in Treg cells in the tumor microenvironment increased with increasing doses of XHP. CONCLUSION XHP might promote Treg cell apoptosis in the tumor microenvironment and further inhibit the tumor growth of 4T1 mouse breast cancer. The mechanism of XHP may be related to upregulation of gene and protein expression of MEKK1, SEK1, JNK1, and AP-1 in Treg cells in the tumor microenvironment.
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Affiliation(s)
- Liang Su
- Xin Hua Affiliated Hospital of Dalian University, Dalian 116000, China
| | - Yiming Jiang
- Xin Hua Affiliated Hospital of Dalian University, Dalian 116000, China
| | - Yu Xu
- Medical College of Dalian University, Dalian 116622, China
| | - Xinye Li
- Medical College of Dalian University, Dalian 116622, China
| | - Wenbin Gao
- Department of Medical Oncology, The 3rd Affiliated Hospital of Shenzhen University, Shenzhen 518001, China
| | - Chunwei Xu
- Department of Pathology, Affiliated Hospital of Academy of Military Medical Sciences, Beijing 100071, China
| | - Changqian Zeng
- Medical College of Dalian University, Dalian 116622, China
| | - Jie Song
- Medical College of Dalian University, Dalian 116622, China
| | - Wencai Weng
- Xin Hua Affiliated Hospital of Dalian University, Dalian 116000, China
| | - Wenbo Liang
- Medical College of Dalian University, Dalian 116622, China.
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Endometrial polyp surveillance in premenopausal breast cancer patients using tamoxifen. Obstet Gynecol Sci 2017; 60:26-31. [PMID: 28217668 PMCID: PMC5313360 DOI: 10.5468/ogs.2017.60.1.26] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Revised: 07/11/2016] [Accepted: 08/03/2016] [Indexed: 11/10/2022] Open
Abstract
Objective To describe the endometrial pathologic lesions in premenopausal breast cancer patients with a history of tamoxifen (TMX) use. Methods We retrospectively reviewed the medical records of 120 premenopausal breast cancer patients with a history of TMX use that had undergone a gynecological examination. Results Among 120 patients, 44.2% (n=53) were asymptomatic with an endometrial thickness ≥5 mm, as assessed by transvaginal ultrasonography. Of the patients that reported abnormal uterine bleeding, 5% (n=6) had an endometrial thickness <5 mm and 20% (n=24) had an endometrial thickness ≥5 mm by transvaginal ultrasonography. The final group of patients were asymptomatic, but showed an abnormal endometrial lesion, such as an endometrial polyp, by transvaginal ultrasonography (30.8%, n=37). Of the 56 benign lesions that were histologically reviewed, 50 (41.7%) were endometrial polyps, 3 (2.5%) were submucosal myomas, 2 (1.7%) were endometrial hyperplasias, and 1 (0.8%) was chronic endometritis. There were 64 (53.3%) other non-pathologic conditions, including secreting, proliferative, and atrophic endometrium, or in some cases, there was insufficient material for diagnosis. In our data, only one case was reported as a complex hyperplasia without atypia arising from an endometrial polyp, and one patient was diagnosed with endometrioid adenocarcinoma. Conclusion For premenopausal breast cancer patients with a history of TMX use, the majority of the patients were asymptomatic, and endometrial polyps were the most common endometrial pathology observed. Therefore, we believe that endometrial assessment before starting TMX treatment, and regular endometrial screening throughout TMX treatment, are reasonable suggestions for premenopausal breast cancer patients.
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Male breast cancer: a clinicopathological study of an Egyptian population (Alexandria experience). Contemp Oncol (Pozn) 2016; 20:335-40. [PMID: 27688732 PMCID: PMC5032163 DOI: 10.5114/wo.2016.61855] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2016] [Accepted: 08/01/2016] [Indexed: 11/17/2022] Open
Abstract
AIM OF THE STUDY The purpose of this retrospective study is to evaluate the clinicopathological features and treatment results of male breast cancer presented to our tertiary referral center. MATERIAL AND METHODS Between January 1998 and December 2005, a total of 39 men with breast cancer treated at Alexandria Main University Hospital and their medical records were reviewed. RESULTS The median age of patients was 59 years. Only 3 (7.7%) patients had positive family history. All patients presented by breast swellings that were associated with axillary mass in about one third of them. Around 80% had hormone receptor positive (estrogen and/or progesterone receptors). Two third of patients had advanced T-stage (T3 and T4). Left sided breast cancer occurred in 51.3%. Infiltrating ductal carcinoma was the most common type of histology encountered and grade 2 was the predominant grade of tumor. Modified radical mastectomy was the most common (87.2%) type of surgery done followed by chemotherapy for 32 patients and loco-regional radiotherapy for 20 patients. Tamoxifen was administered in 31 patients. Distant relapse occurred in 7 patients (17.9%) and local recurrence occurred in 2 patients (5.1%). The 5-year disease-free survival (DFS) was 82% and the 5-year overall survival (OS) rate was 84%. Only negative axillary lymph node and positive hormone receptor status were significantly associated with favorable DFS and OS. T-stage, grade of tumor and type of chemotherapy given had no statistically significant impact on either DFS or OS. CONCLUSIONS Male breast cancer is still under-investigated and further researches are warranted.
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Lumachi F, Santeufemia DA, Basso SMM. Current medical treatment of estrogen receptor-positive breast cancer. World J Biol Chem 2015; 6:231-239. [PMID: 26322178 PMCID: PMC4549764 DOI: 10.4331/wjbc.v6.i3.231] [Citation(s) in RCA: 137] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2015] [Revised: 05/30/2015] [Accepted: 07/23/2015] [Indexed: 02/05/2023] Open
Abstract
Approximately 80% of breast cancers (BC) are estrogen receptor (ER)-positive and thus endocrine therapy (ET) should be considered complementary to surgery in the majority of patients. The advantages of oophorectomy, adrenalectomy and hypophysectomy in women with advanced BC have been demonstrated many years ago, and currently ET consist of (1) ovarian function suppression (OFS), usually obtained using gonadotropin-releasing hormone agonists (GnRHa); (2) selective estrogen receptor modulators or down-regulators (SERMs or SERDs); and (3) aromatase inhibitors (AIs), or a combination of two or more drugs. For patients aged less than 50 years and ER+ BC, there is no conclusive evidence that the combination of OFS and SERMs (i.e., tamoxifen) or chemotherapy is superior to OFS alone. Tamoxifen users exhibit a reduced risk of BC, both invasive and in situ, especially during the first 5 years of therapy, and extending the treatment to 10 years further reduced the risk of recurrences. SERDs (i.e., fulvestrant) are especially useful in the neoadjuvant treatment of advanced BC, alone or in combination with either cytotoxic agents or AIs. There are two types of AIs: type I are permanent steroidal inhibitors of aromatase, while type II are reversible nonsteroidal inhibitors. Several studies demonstrated the superiority of the third-generation AIs (i.e., anastrozole and letrozole) compared with tamoxifen, and adjuvant therapy with AIs reduces the recurrence risk especially in patients with advanced BC. Unfortunately, some cancers are or became ET-resistant, and thus other drugs have been suggested in combination with SERMs or AIs, including cyclin-dependent kinase 4/6 inhibitors (palbociclib) and mammalian target of rapamycin (mTOR) inhibitors, such as everolimus. Further studies are required to confirm their real usefulness.
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Review on the Applications and Molecular Mechanisms of Xihuang Pill in Tumor Treatment. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2015; 2015:854307. [PMID: 26170886 PMCID: PMC4479127 DOI: 10.1155/2015/854307] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/29/2015] [Revised: 05/16/2015] [Accepted: 05/21/2015] [Indexed: 12/17/2022]
Abstract
Xihuang pill (XH) is a complementary and alternative medicine that has been used in traditional Chinese medicine (TCM) for the treatment of tumors since the 18th century. XH has clinical effects on non-Hodgkin lymphoma, breast cancer, gastric cancer, liver cancer, and bone metastasis. XH can also inhibit the growth of tumor cells and cancer stem cells, prevent tumor invasion and angiogenesis, and regulate the tumor microenvironment. XH is composed of Ru Xiang (olibanum), Mo Yao (Commiphora myrrha), She Xiang (Moschus), and Niu Huang (Calculus bovis). Some of the compounds found in these ingredients exert multiple antitumor effects and may synergize with the other ingredients. We aimed to summarize the clinical applications and molecular mechanisms of XH and its chemical composition. This review will provide potential new strategies and alternative perspectives for tumor treatments and basic research into complementary and alternative medicine.
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