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Das GM, Oturkar CC, Menon V. Interaction between Estrogen Receptors and p53: A Broader Role for Tamoxifen? Endocrinology 2025; 166:bqaf020. [PMID: 39891710 PMCID: PMC11837209 DOI: 10.1210/endocr/bqaf020] [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: 09/29/2024] [Revised: 01/20/2025] [Accepted: 01/30/2025] [Indexed: 02/03/2025]
Abstract
Tamoxifen is one of the most widely used anticancer drugs in the world. It is a safe drug with generally well-tolerated side effects and has been prescribed for the treatment of early-stage and advanced-stage or metastatic estrogen receptor α (ERα/ESR1)-positive breast cancer. Tamoxifen therapy also provides a 38% reduction of the risk of developing breast cancer in women at high risk. With the advent of newer medications targeting ERα-positive breast cancer, tamoxifen is now mainly used as adjuvant therapy for lower-risk premenopausal breast cancer and cancer prevention. It is widely accepted that tamoxifen as a selective estrogen receptor modulator exerts its therapeutic effect by competitively binding to ERα, leading to the recruitment of corepressors and inhibition of transcription of genes involved in the proliferation of breast cancer epithelium. As such, expression of ERα in breast tumors has been considered necessary for tumors to be responsive to tamoxifen therapy. However, ERα-independent effects of tamoxifen in various in vitro and in vivo contexts have been reported over the years. Importantly, the recent discovery that ERα and estrogen receptor β (ERβ/ESR2) can bind tumor suppressor protein p53 with functional consequences has provided new insights into the mechanisms underlying response to tamoxifen therapy and resistance. Furthermore, these findings have paved the way for broadening the use of tamoxifen by potentially repurposing it to treat triple negative (negative for ERα, human epidermal growth factor receptor 2, and progesterone receptor) breast cancer. Herein, we summarize these developments and discuss their mechanistic underpinnings and clinical implications.
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Affiliation(s)
- Gokul M Das
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Chetan C Oturkar
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Vishnu Menon
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
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Kumar A, Kaushal A, Verma PK, Gupta MK, Chandra G, Kumar U, Yadav AK, Kumar D. An insight into recent developments in imidazole based heterocyclic compounds as anticancer agents: Synthesis, SARs, and mechanism of actions. Eur J Med Chem 2024; 280:116896. [PMID: 39366252 DOI: 10.1016/j.ejmech.2024.116896] [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: 07/07/2024] [Revised: 09/09/2024] [Accepted: 09/17/2024] [Indexed: 10/06/2024]
Abstract
Among all non-communicable diseases, cancer is ranked as the second most common cause of death and is rising constantly. While cancer treatments mainly include radiation therapy, chemotherapy, and surgery; chemotherapy is considered the most commonly employed and effective treatment. Most of the chemotherapeutic agents are azoles based compounds and imidazole is one such insightful azole. The anticancer properties of imidazole-based compounds have been thoroughly explored in recent years and all monosubstituted, disubstituted, trisubstituted, and tetrasubstituted imidazoles have been explored for their anticancer activities. Along with these compounds, other imidazole-based compounds like 1,3-dihydro-2H-imidazole-2-thiones, imidazolones, and poly imidazole compounds have also been explored for their anticancer activities. The activities of these compounds are heavily influenced by their structural resemblance to combretastatin 4A and ABI (2-aryl-4-benzoyl-imidazole). The lead compounds were highly active on breast, gastric, colon, ovarian, cervical, bone marrow, melanoma, prostate, lung, leukemic, neuroblastoma, liver, Ehrlich, melanoma, and pancreatic cancers. The targets of these leads like tubulin, heme oxygenases, VEGF, tyrosine kinases, EGFR, and others have also been explored. The exploration of the anticancer potential of substituted imidazole compounds is the main topic of this review including synthesis, SAR, and mechanism.
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Affiliation(s)
- Arun Kumar
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Shoolini University, Solan, Himachal Pradesh, 173 229, India
| | - Anjali Kaushal
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Shoolini University, Solan, Himachal Pradesh, 173 229, India; Institute of Pharmaceutical Sciences, Faculty of Pharmacy, Parul University, Vadodara, Gujarat, 391760, India
| | - Prabhakar K Verma
- Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak, 124001, India
| | - Manoj K Gupta
- Department of Chemistry, Central University of Haryana, Mahendergarh, Haryana, 123031, India
| | - Girish Chandra
- Department of Chemistry, School of Physical and Chemical Sciences, Central University of South Bihar, Gaya, Bihar, 824236, India
| | - Umesh Kumar
- Catalysis and Bioinorganic Research Lab, Department of Chemistry, Deshbandhu College, University of Delhi, New Delhi, 110019, India
| | - Ashok K Yadav
- University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India
| | - Deepak Kumar
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Shoolini University, Solan, Himachal Pradesh, 173 229, India.
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Gu L, Pillay RP, Aronson R, Kaur M. Cholesteryl ester transfer protein knock-down in conjunction with a cholesterol-depleting agent decreases tamoxifen resistance in breast cancer cells. IUBMB Life 2024; 76:712-730. [PMID: 38733508 DOI: 10.1002/iub.2823] [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: 02/05/2024] [Accepted: 03/25/2024] [Indexed: 05/13/2024]
Abstract
The cholesterogenic phenotype, encompassing de novo biosynthesis and accumulation of cholesterol, aids cancer cell proliferation and survival. Previously, the role of cholesteryl ester (CE) transfer protein (CETP) has been implicated in breast cancer aggressiveness, but the molecular basis of this observation is not clearly understood, which this study aims to elucidate. CETP knock-down resulted in a >50% decrease in cell proliferation in both 'estrogen receptor-positive' (ER+; Michigan Cancer Foundation-7 (MCF7) breast cancer cells) and 'triple-negative' breast cancer (TNBC; MDA-MB-231) cell lines. Intriguingly, the abrogation of CETP together with the combination treatment of tamoxifen (5 μM) and acetyl plumbagin (a cholesterol-depleting agent) (5 μM) resulted in twofold to threefold increase in apoptosis in both cell lines. CETP knockdown also showed decreased intracellular CE levels, lipid raft and lipid droplets in both cell lines. In addition, RT2 Profiler PCR array (Qiagen, Germany)-based gene expression analysis revealed an overall downregulation of genes associated in cholesterol biosynthesis, lipid signalling and drug resistance in MCF7 cells post-CETP knock-down. On the contrary, resistance in MDA-MB-231 cells was reduced through increased expression in cholesterol efflux genes and the expression of targetable surface receptors by endocrine therapy. The pilot xenograft mice study substantiated CETP's role as a cancer survival gene as knock-down of CETP stunted the growth of TNBC tumour by 86%. The principal findings of this study potentiate CETP as a driver in breast cancer growth and aggressiveness and thus targeting CETP could limit drug resistance via the reduction in cholesterol accumulation in breast cancer cells, thereby reducing cancer aggressiveness.
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Affiliation(s)
- Liang Gu
- Department of School of Molecular and Cell Biology, University of the Witwatersrand, Johannesburg, South Africa
| | - Ruvesh Pascal Pillay
- Department of School of Molecular and Cell Biology, University of the Witwatersrand, Johannesburg, South Africa
| | - Ruth Aronson
- Department of School of Molecular and Cell Biology, University of the Witwatersrand, Johannesburg, South Africa
| | - Mandeep Kaur
- Department of School of Molecular and Cell Biology, University of the Witwatersrand, Johannesburg, South Africa
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Wang D, Tang M, Zhang P, Yang K, Huang L, Wu M, Shen Q, Yue J, Wang W, Gong Y, Warner M, Dai L, He H, Yang Z, Gustafsson JA, Zhou S. Activation of ERβ hijacks the splicing machinery to trigger R-loop formation in triple-negative breast cancer. Proc Natl Acad Sci U S A 2024; 121:e2306814121. [PMID: 38513102 PMCID: PMC10990146 DOI: 10.1073/pnas.2306814121] [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: 04/26/2023] [Accepted: 01/23/2024] [Indexed: 03/23/2024] Open
Abstract
Triple-negative breast cancer (TNBC) is a subtype of breast cancer with aggressive behavior and poor prognosis. Current therapeutic options available for TNBC patients are primarily chemotherapy. With our evolving understanding of this disease, novel targeted therapies, including poly ADP-ribose polymerase (PARP) inhibitors, antibody-drug conjugates, and immune-checkpoint inhibitors, have been developed for clinical use. Previous reports have demonstrated the essential role of estrogen receptor β (ERβ) in TNBC, but the detailed molecular mechanisms downstream ERβ activation in TNBC are still far from elucidated. In this study, we demonstrated that a specific ERβ agonist, LY500307, potently induces R-loop formation and DNA damage in TNBC cells. Subsequent interactome experiments indicated that the residues 151 to 165 of U2 small nuclear RNA auxiliary factor 1 (U2AF1) and the Trp439 and Lys443 of ERβ were critical for the binding between U2AF1 and ERβ. Combined RNA sequencing and ribosome sequencing analysis demonstrated that U2AF1-regulated downstream RNA splicing of 5-oxoprolinase (OPLAH) could affect its enzymatic activity and is essential for ERβ-induced R-loop formation and DNA damage. In clinical samples including 115 patients from The Cancer Genome Atlas (TCGA) and 32 patients from an in-house cohort, we found a close correlation in the expression of ESR2 and U2AF1 in TNBC patients. Collectively, our study has unraveled the molecular mechanisms that explain the therapeutic effects of ERβ activation in TNBC, which provides rationale for ERβ activation-based single or combined therapy for patients with TNBC.
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Affiliation(s)
- Dongfang Wang
- Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education and State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University and Collaborative Innovation Center, Chengdu610041, People’s Republic of China
| | - Muya Tang
- Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education and State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University and Collaborative Innovation Center, Chengdu610041, People’s Republic of China
| | - Peidong Zhang
- Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education and State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University and Collaborative Innovation Center, Chengdu610041, People’s Republic of China
| | - Kailin Yang
- Department of Radiation Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH44106
| | - Liang Huang
- Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education and State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University and Collaborative Innovation Center, Chengdu610041, People’s Republic of China
| | - Mengrui Wu
- Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education and State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University and Collaborative Innovation Center, Chengdu610041, People’s Republic of China
| | - Qiuhong Shen
- Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education and State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University and Collaborative Innovation Center, Chengdu610041, People’s Republic of China
| | - Jing Yue
- Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education and State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University and Collaborative Innovation Center, Chengdu610041, People’s Republic of China
| | - Wei Wang
- Department of Gynecology, Biomedical Big Data Center, Huzhou Maternity and Child Health Care Hospital, Huzhou, Zhejiang313000, People’s Republic of China
| | - Yanqiu Gong
- National Clinical Research Center for Geriatrics and General Practice Medical Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu610041, People’s Republic of China
| | - Margaret Warner
- Department of Biology and Biochemistry, Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX77204
| | - Lunzhi Dai
- National Clinical Research Center for Geriatrics and General Practice Medical Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu610041, People’s Republic of China
| | - Haihuai He
- Department of Neurosurgery, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu610041, People’s Republic of China
| | - Zhengnan Yang
- Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education and State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University and Collaborative Innovation Center, Chengdu610041, People’s Republic of China
| | - Jan-Ake Gustafsson
- Department of Biology and Biochemistry, Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX77204
- Department of Biosciences and Nutrition, Karolinska Institute, Huddinge14157, Sweden
| | - Shengtao Zhou
- Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education and State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University and Collaborative Innovation Center, Chengdu610041, People’s Republic of China
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Xu F, Xu K, Fan L, Li X, Liu Y, Yang F, Zhu C, Guan X. Estrogen receptor beta suppresses the androgen receptor oncogenic effects in triple-negative breast cancer. Chin Med J (Engl) 2024; 137:338-349. [PMID: 38105538 PMCID: PMC10836903 DOI: 10.1097/cm9.0000000000002930] [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: 05/31/2023] [Indexed: 12/19/2023] Open
Abstract
BACKGROUND Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer associated with poor prognosis and limited treatment options. The androgen receptor (AR) has emerged as a potential therapeutic target for luminal androgen receptor (LAR) TNBC. However, multiple studies have claimed that anti-androgen therapy for AR-positive TNBC only has limited clinical benefits. This study aimed to investigate the role of AR in TNBC and its detailed mechanism. METHODS Immunohistochemistry and TNBC tissue sections were applied to investigate AR and nectin cell adhesion molecule 4 (NECTIN4) expression in TNBC tissues. Then, in vitro and in vivo assays were used to explore the function of AR and estrogen receptor beta (ERβ) in TNBC. Chromatin immunoprecipitation sequencing (ChIP-seq), co-immunoprecipitation (co-IP), molecular docking method, and luciferase reporter assay were performed to identify key molecules that affect the function of AR. RESULTS Based on the TNBC tissue array analysis, we revealed that ERβ and AR were positive in 21.92% (32/146) and 24.66% (36/146) of 146 TNBC samples, respectively, and about 13.70% (20/146) of TNBC patients were ERβ positive and AR positive. We further demonstrated the pro-tumoral effects of AR on TNBC cells, however, the oncogenic biology was significantly suppressed when ERβ transfection in LAR TNBC cell lines but not in AR-negative TNBC. Mechanistically, we identified that NECTIN4 promoter -42 bp to -28 bp was an AR response element, and that ERβ interacted with AR thus impeding the AR-mediated NECTIN4 transcription which promoted epithelial-mesenchymal transition in tumor progression. CONCLUSIONS This study suggests that ERβ functions as a suppressor mediating the effect of AR in TNBC prognosis and cell proliferation. Therefore, our current research facilitates a better understanding of the role and mechanisms of AR in TNBC carcinogenesis.
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Affiliation(s)
- Feng Xu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Kun Xu
- Department of Oncology, Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Institute of Cancer Research, Nanjing, Jiangsu 210009, China
| | - Lingling Fan
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Xintong Li
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Yiqiu Liu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Fang Yang
- The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu 210008, China
| | - Chengjun Zhu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Xiaoxiang Guan
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, China
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Crespo B, Illera JC, Silvan G, Lopez-Plaza P, Herrera de la Muela M, de la Puente Yagüe M, Diaz del Arco C, Illera MJ, Caceres S. Androgen and Estrogen β Receptor Expression Enhances Efficacy of Antihormonal Treatments in Triple-Negative Breast Cancer Cell Lines. Int J Mol Sci 2024; 25:1471. [PMID: 38338747 PMCID: PMC10855276 DOI: 10.3390/ijms25031471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 01/10/2024] [Accepted: 01/20/2024] [Indexed: 02/12/2024] Open
Abstract
The triple-negative breast cancer (TNBC) subtype is characterized by the lack of expression of ERα (estrogen receptor α), PR (progesterone receptor) and no overexpression of HER-2. However, TNBC can express the androgen receptor (AR) or estrogen receptor β (ERβ). Also, TNBC secretes steroid hormones and is influenced by hormonal fluctuations, so the steroid inhibition could exert a beneficial effect in TNBC treatment. The aim of this study was to evaluate the effect of dutasteride, anastrozole and ASP9521 in in vitro processes using human TNBC cell lines. For this, immunofluorescence, sensitivity, proliferation and wound healing assays were performed, and hormone concentrations were studied. Results revealed that all TNBC cell lines expressed AR and ERβ; the ones that expressed them most intensely were more sensitive to antihormonal treatments. All treatments reduced cell viability, highlighting MDA-MB-453 and SUM-159. Indeed, a decrease in androgen levels was observed in these cell lines, which could relate to a reduction in cell viability. In addition, MCF-7 and SUM-159 increased cell migration under treatments, increasing estrogen levels, which could favor cell migration. Thus, antihormonal treatments could be beneficial for TNBC therapies. This study clarifies the importance of steroid hormones in AR and ERβ-positive cell lines of TNBC.
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Affiliation(s)
- Belen Crespo
- Department Animal Physiology, Veterinary Medicine School, Complutense University of Madrid (UCM), 28040 Madrid, Spain; (B.C.); (G.S.); (P.L.-P.); (M.J.I.); (S.C.)
| | - Juan Carlos Illera
- Department Animal Physiology, Veterinary Medicine School, Complutense University of Madrid (UCM), 28040 Madrid, Spain; (B.C.); (G.S.); (P.L.-P.); (M.J.I.); (S.C.)
| | - Gema Silvan
- Department Animal Physiology, Veterinary Medicine School, Complutense University of Madrid (UCM), 28040 Madrid, Spain; (B.C.); (G.S.); (P.L.-P.); (M.J.I.); (S.C.)
| | - Paula Lopez-Plaza
- Department Animal Physiology, Veterinary Medicine School, Complutense University of Madrid (UCM), 28040 Madrid, Spain; (B.C.); (G.S.); (P.L.-P.); (M.J.I.); (S.C.)
| | - María Herrera de la Muela
- Obstetrics and Gynecology Department, Hospital Clinico San Carlos, Instituto de Salud de la Mujer, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IsISSC), 28040 Madrid, Spain;
| | - Miriam de la Puente Yagüe
- Department of Public and Maternal Child Health University, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain;
| | | | - Maria Jose Illera
- Department Animal Physiology, Veterinary Medicine School, Complutense University of Madrid (UCM), 28040 Madrid, Spain; (B.C.); (G.S.); (P.L.-P.); (M.J.I.); (S.C.)
| | - Sara Caceres
- Department Animal Physiology, Veterinary Medicine School, Complutense University of Madrid (UCM), 28040 Madrid, Spain; (B.C.); (G.S.); (P.L.-P.); (M.J.I.); (S.C.)
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Kirkby M, Popatia AM, Lavoie JR, Wang L. The Potential of Hormonal Therapies for Treatment of Triple-Negative Breast Cancer. Cancers (Basel) 2023; 15:4702. [PMID: 37835396 PMCID: PMC10571841 DOI: 10.3390/cancers15194702] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 09/18/2023] [Accepted: 09/22/2023] [Indexed: 10/15/2023] Open
Abstract
Triple-negative breast cancer (TNBC) is considered one of the most aggressive forms of breast cancer with poor survival rates compared to other breast cancer subtypes. TNBC is characterized by the absence of the estrogen receptor alpha, progesterone receptor, and the human epidermal growth factor receptor 2, limiting those viable treatment options available to patients with other breast cancer subtypes. Furthermore, due to the particularly high heterogeneity of TNBC, conventional treatments such as chemotherapy are not universally effective, leading to drug resistance and intolerable side effects. Thus, there is a pressing need to discover new therapies beneficial to TNBC patients. This review highlights current findings regarding the roles of three steroid hormone receptors, estrogen receptor beta, the androgen receptor, and the glucocorticoid receptor, in the progression of TNBC. In addition, we discussed several ongoing and completed clinical trials targeting these hormone receptors in TNBC patients.
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Affiliation(s)
- Melanie Kirkby
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada; (M.K.); (A.M.P.)
- Ottawa Institute of Systems Biology, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada
- The Centre for Infection, Immunity, and Inflammation (CI3), University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada
- Centre for Oncology, Radiopharmaceuticals and Research, Biologic and Radiopharmaceutical Drugs Directorate, Health Products and Food Branch, Health Canada, Ottawa, ON K1A 0K9, Canada
| | - Alyanna M. Popatia
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada; (M.K.); (A.M.P.)
- Ottawa Institute of Systems Biology, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada
- The Centre for Infection, Immunity, and Inflammation (CI3), University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada
| | - Jessie R. Lavoie
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada; (M.K.); (A.M.P.)
- Centre for Oncology, Radiopharmaceuticals and Research, Biologic and Radiopharmaceutical Drugs Directorate, Health Products and Food Branch, Health Canada, Ottawa, ON K1A 0K9, Canada
| | - Lisheng Wang
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada; (M.K.); (A.M.P.)
- Ottawa Institute of Systems Biology, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada
- The Centre for Infection, Immunity, and Inflammation (CI3), University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada
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Belluti S, Imbriano C, Casarini L. Nuclear Estrogen Receptors in Prostate Cancer: From Genes to Function. Cancers (Basel) 2023; 15:4653. [PMID: 37760622 PMCID: PMC10526871 DOI: 10.3390/cancers15184653] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 09/01/2023] [Accepted: 09/18/2023] [Indexed: 09/29/2023] Open
Abstract
Estrogens are almost ubiquitous steroid hormones that are essential for development, metabolism, and reproduction. They exert both genomic and non-genomic action through two nuclear receptors (ERα and ERβ), which are transcription factors with disregulated functions and/or expression in pathological processes. In the 1990s, the discovery of an additional membrane estrogen G-protein-coupled receptor augmented the complexity of this picture. Increasing evidence elucidating the specific molecular mechanisms of action and opposing effects of ERα and Erβ was reported in the context of prostate cancer treatment, where these issues are increasingly investigated. Although new approaches improved the efficacy of clinical therapies thanks to the development of new molecules targeting specifically estrogen receptors and used in combination with immunotherapy, more efforts are needed to overcome the main drawbacks, and resistance events will be a challenge in the coming years. This review summarizes the state-of-the-art on ERα and ERβ mechanisms of action in prostate cancer and promising future therapies.
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Affiliation(s)
- Silvia Belluti
- Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy; (S.B.); (C.I.)
| | - Carol Imbriano
- Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy; (S.B.); (C.I.)
| | - Livio Casarini
- Unit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Ospedale di Baggiovara, 41126 Modena, Italy
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Takano EA, Younes MM, Meehan K, Spalding L, Yan M, Allan P, Fox SB, Redfern A, Clouston D, Giles GG, Christie EL, Anderson RL, Zethoven M, Phillips KA, Gorringe K, Britt KL. Estrogen receptor beta expression in triple negative breast cancers is not associated with recurrence or survival. BMC Cancer 2023; 23:459. [PMID: 37208678 DOI: 10.1186/s12885-023-10795-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 03/31/2023] [Indexed: 05/21/2023] Open
Abstract
BACKGROUND Triple negative BCa (TNBC) is defined by a lack of expression of estrogen (ERα), progesterone (PgR) receptors and human epidermal growth factor receptor 2 (HER2) as assessed by protein expression and/or gene amplification. It makes up ~ 15% of all BCa and often has a poor prognosis. TNBC is not treated with endocrine therapies as ERα and PR negative tumors in general do not show benefit. However, a small fraction of the true TNBC tumors do show tamoxifen sensitivity, with those expressing the most common isoform of ERβ1 having the most benefit. Recently, the antibodies commonly used to assess ERβ1 in TNBC have been found to lack specificity, which calls into question available data regarding the proportion of TNBC that express ERβ1 and any relationship to clinical outcome. METHODS To confirm the true frequency of ERβ1 in TNBC we performed robust ERβ1 immunohistochemistry using the specific antibody CWK-F12 ERβ1 on 156 primary TNBC cancers from patients with a median of 78 months (range 0.2-155 months) follow up. RESULTS We found that high expression of ERβ1 was not associated with increased recurrence or survival when assessed as percentage of ERβ1 positive tumor cells or as Allred > 5. In contrast, the non-specific PPG5-10 antibody did show an association with recurrence and survival. CONCLUSIONS Our data indicate that ERβ1 expression in TNBC tumours does not associate with prognosis.
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Affiliation(s)
- Elena A Takano
- Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia
| | - Melissa M Younes
- Breast Cancer Risk and Prevention Laboratory, Peter MacCallum Cancer Centre, Research Division 305 Grattan St, Melbourne, VIC, 3000, Australia
| | - Katie Meehan
- Department of Otorhinolaryngology, Head and Neck Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong
- The University of Western Australia (M504), 35 Stirling Highway, Perth, 6009, Australia
| | - Lisa Spalding
- The University of Western Australia (M504), 35 Stirling Highway, Perth, 6009, Australia
| | - Max Yan
- South Eastern Area Laboratory Services, Randwick, NSW, Australia
| | - Prue Allan
- Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia
| | - Stephen B Fox
- Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia
- School of Cancer Medicine, La Trobe University, Bundoora, VIC, 3086, Australia
| | - Andy Redfern
- The University of Western Australia (M504), 35 Stirling Highway, Perth, 6009, Australia
| | - David Clouston
- TissuPath, 32 Ricketts Rd, Mount Waverley, VIC, 3149, Australia
| | - Graham G Giles
- 7a Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, 3004, Australia
- Centre for Epidemiology and Biostatistics, School of Population and Global Health, University of Melbourne, Parkville, VIC, 3012, Australia
- Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, 3168, Australia
| | - Elizabeth L Christie
- School of Cancer Medicine, La Trobe University, Bundoora, VIC, 3086, Australia
- Peter MacCallum Cancer Centre Melbourne, Victoria, 3000, Australia
| | - Robin L Anderson
- School of Cancer Medicine, La Trobe University, Bundoora, VIC, 3086, Australia
- Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, 3084, Australia
- The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia
| | - Magnus Zethoven
- The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia
- Peter Mac, Bioinformatics Core Facility, Peter MacCallum Cancer Centre, 305 Grattan St, Melbourne, VIC, Australia
| | - Kelly-Anne Phillips
- The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia
- Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
- Centre for Epidemiology and Biostatistics, School of Population and Global Health, The University of Melbourne, Parkville, VIC, Australia
| | - Kylie Gorringe
- The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia
- Precision Cancer Medicine Laboratory, Peter MacCallum Cancer Centre, 305 Grattan St, Melbourne, VIC, Australia
| | - Kara L Britt
- Breast Cancer Risk and Prevention Laboratory, Peter MacCallum Cancer Centre, Research Division 305 Grattan St, Melbourne, VIC, 3000, Australia.
- The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia.
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10
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Zárate LV, Miret NV, Nicola Candia AJ, Zappia CD, Pontillo CA, Chiappini FA, Monczor F, Candolfi M, Randi AS. Breast cancer progression and kynurenine pathway enzymes are induced by hexachlorobenzene exposure in a Her2-positive model. Food Chem Toxicol 2023; 177:113822. [PMID: 37169060 DOI: 10.1016/j.fct.2023.113822] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 05/05/2023] [Accepted: 05/08/2023] [Indexed: 05/13/2023]
Abstract
Breast cancer is one of the leading cancers among women worldwide. Given the evidence that pesticides play an important role in breast cancer, interest has grown in pesticide impact on disease progression. Hexachlorobenzene (HCB), an aryl hydrocarbon receptor (AhR) ligand, promotes triple-negative breast cancer cell migration and invasion. Estrogen receptor β (ERβ) inhibits cancer motility, while G protein-coupled ER (GPER) modulates the neoplastic transformation. Tryptophan is metabolized through the kynurenine pathway by indoleamine-2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO), with kynurenine signaling activation often predicting worse prognosis in cancer. In this context, we examined the HCB (0.005; 0.05; 0.5 and 5 μM) effect on LM3 cells, a human epidermal growth factor receptor 2 (HER2)-positive breast cancer model. Results show that HCB increases IDO and TDO mRNA levels and promotes cell viability, proliferation and migration through the AhR pathway. Moreover, HCB boosts mammosphere formation, vascular endothelial growth factor and cyclooxygenase-2 expression and reduces IL-10 levels. For some parameters, U-shaped or inverted U-shaped dose-response curves are shown. HCB alters ER levels, reducing ERβ while increasing GPER. These results demonstrate that exposure to environmentally relevant concentrations of HCB up-regulates the kynurenine pathway and dysregulates ERβ and GPER levels, collaborating in HER2-positive breast cancer progression.
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Affiliation(s)
- Lorena V Zárate
- Universidad de Buenos Aires, Facultad de Medicina, Departamento de Bioquímica Humana, Laboratorio de Efectos Biológicos de Contaminants Ambientales, Paraguay 2155, Piso 5, (CP 1121), Buenos Aires, Argentina.
| | - Noelia V Miret
- Universidad de Buenos Aires, Facultad de Medicina, Departamento de Bioquímica Humana, Laboratorio de Efectos Biológicos de Contaminants Ambientales, Paraguay 2155, Piso 5, (CP 1121), Buenos Aires, Argentina; Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Físico-Matemática, Laboratorio de Radioisótopos, Junín 954, 1er Subsuelo, (CP 1121), Buenos Aires, Argentina.
| | - Alejandro J Nicola Candia
- Universidad de Buenos Aires, Facultad de Medicina, Instituto de Investigaciones Biomédicas, Laboratorio de Inmunoterapia Antitumoral, Paraguay 2155, Piso 10, (CP 1121), Buenos Aires, Argentina.
| | - C Daniel Zappia
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Instituto de Investigaciones Farmacológicas (UBA-CONICET), Laboratorio de Farmacología de Receptors, Junín 954, Planta Baja, (CP1113), Buenos Aires, Argentina.
| | - Carolina A Pontillo
- Universidad de Buenos Aires, Facultad de Medicina, Departamento de Bioquímica Humana, Laboratorio de Efectos Biológicos de Contaminants Ambientales, Paraguay 2155, Piso 5, (CP 1121), Buenos Aires, Argentina.
| | - Florencia A Chiappini
- Universidad de Buenos Aires, Facultad de Medicina, Departamento de Bioquímica Humana, Laboratorio de Efectos Biológicos de Contaminants Ambientales, Paraguay 2155, Piso 5, (CP 1121), Buenos Aires, Argentina.
| | - Federico Monczor
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Instituto de Investigaciones Farmacológicas (UBA-CONICET), Laboratorio de Farmacología de Receptors, Junín 954, Planta Baja, (CP1113), Buenos Aires, Argentina.
| | - Marianela Candolfi
- Universidad de Buenos Aires, Facultad de Medicina, Instituto de Investigaciones Biomédicas, Laboratorio de Inmunoterapia Antitumoral, Paraguay 2155, Piso 10, (CP 1121), Buenos Aires, Argentina.
| | - Andrea S Randi
- Universidad de Buenos Aires, Facultad de Medicina, Departamento de Bioquímica Humana, Laboratorio de Efectos Biológicos de Contaminants Ambientales, Paraguay 2155, Piso 5, (CP 1121), Buenos Aires, Argentina.
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11
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Scarpetti L, Oturkar CC, Juric D, Shellock M, Malvarosa G, Post K, Isakoff S, Wang N, Nahed B, Oh K, Das GM, Bardia A. Therapeutic Role of Tamoxifen for Triple-Negative Breast Cancer: Leveraging the Interaction Between ERβ and Mutant p53. Oncologist 2023; 28:358-363. [PMID: 36772966 PMCID: PMC10078911 DOI: 10.1093/oncolo/oyac281] [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: 06/14/2022] [Accepted: 10/30/2022] [Indexed: 02/12/2023] Open
Abstract
The absence of effective therapeutic targets and aggressive nature of triple-negative breast cancer (TNBC) renders this disease subset difficult to treat. Although estrogen receptor beta (ERβ) is expressed in TNBC, studies on its functional role have yielded inconsistent results. However, recently, our preclinical studies, along with other observations, have shown the potential therapeutic utility of ERβ in the context of mutant p53 expression. The current case study examines the efficacy of the selective estrogen receptor modulator tamoxifen in p53-mutant TNBC with brain metastases. Significant increase in ERβ protein expression and anti-proliferative interaction between mutant p53 and ERβ were observed after cessation of tamoxifen therapy, with significant regression of brain metastases. This case study provides supporting evidence for the use of tamoxifen in p53-mutant, ERβ+TNBC, especially in the setting of brain metastasis.
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Affiliation(s)
- Lauren Scarpetti
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA
| | | | - Dejan Juric
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA
| | - Maria Shellock
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA
| | - Giuliana Malvarosa
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA
| | - Kathryn Post
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA
| | - Steven Isakoff
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA
| | - Nancy Wang
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA
| | - Brian Nahed
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA
| | - Kevin Oh
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA
| | - Gokul M Das
- Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Aditya Bardia
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA
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12
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Meligova AK, Siakouli D, Stasinopoulou S, Xenopoulou DS, Zoumpouli M, Ganou V, Gkotsi EF, Chatziioannou A, Papadodima O, Pilalis E, Alexis MN, Mitsiou DJ. ERβ1 Sensitizes and ERβ2 Desensitizes ERα-Positive Breast Cancer Cells to the Inhibitory Effects of Tamoxifen, Fulvestrant and Their Combination with All-Trans Retinoic Acid. Int J Mol Sci 2023; 24:ijms24043747. [PMID: 36835157 PMCID: PMC9959521 DOI: 10.3390/ijms24043747] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 02/07/2023] [Accepted: 02/10/2023] [Indexed: 02/16/2023] Open
Abstract
Adjuvant endocrine therapy (AET) is the treatment of choice for early-stage estrogen receptor alpha (ERα)-positive breast cancer (BC). However, almost 40% of tamoxifen-treated cases display no response or a partial response to AET, thus increasing the need for new treatment options and strong predictors of the therapeutic response of patients at high risk of relapse. In addition to ERα, BC research has focused on ERβ1 and ERβ2 (isoforms of ERβ), the second ER isotype. At present, the impact of ERβ isoforms on ERα-positive BC prognosis and treatment remains elusive. In the present study, we established clones of MCF7 cells constitutively expressing human ERβ1 or ERβ2 and investigated their role in the response of MCF7 cells to antiestrogens [4-hydroxytamoxifen (OHΤ) and fulvestrant (ICI182,780)] and retinoids [all-trans retinoic acid (ATRA)]. We show that, compared to MCF7 cells, MCF7-ERβ1 and MCF7-ERβ2 cells were sensitized and desensitized, respectively, to the antiproliferative effect of the antiestrogens, ATRA and their combination and to the cytocidal effect of the combination of OHT and ATRA. Analysis of the global transcriptional changes upon OHT-ATRA combinatorial treatment revealed uniquely regulated genes associated with anticancer effects in MCF7-ERβ1 cells and cancer-promoting effects in MCF7-ERβ2 cells. Our data are favorable to ERβ1 being a marker of responsiveness and ERβ2 being a marker of resistance of MCF7 cells to antiestrogens alone and in combination with ATRA.
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Affiliation(s)
- Aggeliki K. Meligova
- Institute of Chemical Biology, National Hellenic Research Foundation, 11635 Athens, Greece
| | - Dimitra Siakouli
- Institute of Chemical Biology, National Hellenic Research Foundation, 11635 Athens, Greece
| | - Sotiria Stasinopoulou
- Institute of Chemical Biology, National Hellenic Research Foundation, 11635 Athens, Greece
| | - Despoina S. Xenopoulou
- Institute of Chemical Biology, National Hellenic Research Foundation, 11635 Athens, Greece
| | - Maria Zoumpouli
- Institute of Chemical Biology, National Hellenic Research Foundation, 11635 Athens, Greece
| | - Vassiliki Ganou
- Institute of Chemical Biology, National Hellenic Research Foundation, 11635 Athens, Greece
| | - Eleni-Fani Gkotsi
- Institute of Chemical Biology, National Hellenic Research Foundation, 11635 Athens, Greece
| | - Aristotelis Chatziioannou
- Center of Systems Biology, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece
| | - Olga Papadodima
- Institute of Chemical Biology, National Hellenic Research Foundation, 11635 Athens, Greece
| | | | - Michael N. Alexis
- Institute of Chemical Biology, National Hellenic Research Foundation, 11635 Athens, Greece
- Correspondence: (M.N.A.); (D.J.M.)
| | - Dimitra J. Mitsiou
- Institute of Chemical Biology, National Hellenic Research Foundation, 11635 Athens, Greece
- Correspondence: (M.N.A.); (D.J.M.)
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13
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Neonatal feeding of an estrogen receptor β agonist induces external adenomyosis-like lesions in ICR mouse. REPRODUCTIVE AND DEVELOPMENTAL MEDICINE 2022. [DOI: 10.1097/rd9.0000000000000012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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14
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Jinna N, Rida P, Smart M, LaBarge M, Jovanovic-Talisman T, Natarajan R, Seewaldt V. Adaptation to Hypoxia May Promote Therapeutic Resistance to Androgen Receptor Inhibition in Triple-Negative Breast Cancer. Int J Mol Sci 2022; 23:ijms23168844. [PMID: 36012111 PMCID: PMC9408190 DOI: 10.3390/ijms23168844] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 08/03/2022] [Accepted: 08/06/2022] [Indexed: 12/27/2022] Open
Abstract
Triple-negative breast cancer (TNBC) surpasses other BC subtypes as the most challenging to treat due to its lack of traditional BC biomarkers. Nearly 30% of TNBC patients express the androgen receptor (AR), and the blockade of androgen production and AR signaling have been the cornerstones of therapies for AR-positive TNBC. However, the majority of women are resistant to AR-targeted therapy, which is a major impediment to improving outcomes for the AR-positive TNBC subpopulation. The hypoxia signaling cascade is frequently activated in the tumor microenvironment in response to low oxygen levels; activation of the hypoxia signaling cascade allows tumors to survive despite hypoxia-mediated interference with cellular metabolism. The activation of hypoxia signaling networks in TNBC promotes resistance to most anticancer drugs including AR inhibitors. The activation of hypoxia network signaling occurs more frequently in TNBC compared to other BC subtypes. Herein, we examine the (1) interplay between hypoxia signaling networks and AR and (2) whether hypoxia and hypoxic stress adaptive pathways promote the emergence of resistance to therapies that target AR. We also pose the well-supported question, “Can the efficacy of androgen-/AR-targeted treatments be enhanced by co-targeting hypoxia?” By critically examining the evidence and the complex entwinement of these two oncogenic pathways, we argue that the simultaneous targeting of androgen biosynthesis/AR signaling and hypoxia may enhance the sensitivity of AR-positive TNBCs to AR-targeted treatments, derail the emergence of therapy resistance, and improve patient outcomes.
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Affiliation(s)
- Nikita Jinna
- Department of Population Science, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
| | | | - Max Smart
- Rowland Hall, Salt Lake City, UT 84102, USA
| | - Mark LaBarge
- Department of Population Science, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
| | | | - Rama Natarajan
- Department of Diabetes Complications and Metabolism, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
| | - Victoria Seewaldt
- Department of Population Science, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
- Correspondence:
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15
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Jeun SE, Kim GH, Lee MW, Lee S. Metastasis of breast cancer presenting as enlarged folds in the stomach. Clin Endosc 2022; 55:463-464. [PMID: 33153252 PMCID: PMC9178130 DOI: 10.5946/ce.2020.239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 09/11/2020] [Accepted: 09/12/2020] [Indexed: 11/14/2022] Open
Affiliation(s)
- So Eun Jeun
- Department of Internal Medicine, Pusan National University College of Medicine, Busan, Korea
| | - Gwang Ha Kim
- Department of Internal Medicine, Pusan National University College of Medicine, Busan, Korea
- Biomedical Research Institute, Pusan National University Hospital, Busan, Korea
| | - Moon Won Lee
- Department of Internal Medicine, Pusan National University College of Medicine, Busan, Korea
- Biomedical Research Institute, Pusan National University Hospital, Busan, Korea
| | - Sojeong Lee
- Department of Pathology, Pusan National University College of Medicine, Busan, Korea
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16
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ERβ Isoforms Have Differential Clinical Significance in Breast Cancer Subtypes and Subgroups. Curr Issues Mol Biol 2022; 44:1564-1586. [PMID: 35723365 PMCID: PMC9164084 DOI: 10.3390/cimb44040107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 03/31/2022] [Accepted: 04/01/2022] [Indexed: 12/02/2022] Open
Abstract
ERβ, an ER subtype first identified in 1996, is highly expressed in different types of BCa including ERα-negative BCa and TNBC. Many studies on ERβ expression investigated mostly on ERβ1 protein expression in ERα-positive and ERα-negative BCa combined. The results are conflicting. This may be due to the complexity of ERβ isoforms, subject heterogeneity, and various study designs targeting different ERβ isoforms and either ERβ protein or mRNA expression, as well as to the lack of a standardized testing protocol. Herein, we simultaneously investigated both mRNA and protein expression of ERβ isoforms 1, 2, and 5 in different BCa subtypes and clinical characteristics. Patient samples (138) and breast cancer cell lines (BCC) reflecting different types of BCa were tested for ERα and ERβ mRNA expression using quantitative real-time PCR, as well as for protein expression of ERα, ERβ1, ERβ2, and ERβ5 isoforms, PR, HER2/neu, Ki-67, CK 5/6, and p53 using immunohistochemistry. Associations of ERβ isoform expression with clinical characteristics and overall survival (OS) were analyzed. ERβ1, 2, and 5 isoforms are differentially expressed in different BCa subtypes including ERα-negative and TNBC. Each ERβ isoform seemingly plays a distinct role and is associated with clinical tumor characteristics and patient outcomes. ERβ isoform expression is significantly associated with >15% Ki-67 positivity and poor prognostic markers, and it predicts poorer OS, mostly in the subgroups. High ERβ2 and 5 isoform expression in ERα-negative BCa and TNBC is predictive of poor OS. Further investigation of ERβ isoforms in a larger cohort of BCa subgroups is needed to evaluate the role of ERβ for the potential usefulness of ERβ as a prognostic and predictive marker and for therapeutic use. The inconsistent outcomes of ERβ isoform mRNA or protein expression in many studies suggest that the standardization of ERβ testing would facilitate the use of ERβ in a clinical setting.
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17
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Unveiling the Pathogenesis of Adenomyosis through Animal Models. J Clin Med 2022; 11:jcm11061744. [PMID: 35330066 PMCID: PMC8953406 DOI: 10.3390/jcm11061744] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 03/09/2022] [Accepted: 03/15/2022] [Indexed: 02/08/2023] Open
Abstract
Background: Adenomyosis is a common gynecological disorder traditionally viewed as “elusive”. Several excellent review papers have been published fairly recently on its pathogenesis, and several theories have been proposed. However, the falsifiability, explanatory power, and predictivity of these theories are often overlooked. Since adenomyosis can occur spontaneously in rodents and many other species, the animal models may help us unveil the pathogenesis of adenomyosis. This review critically tallies experimentally induced models published so far, with a particular focus on their relevance to epidemiological findings, their possible mechanisms of action, and their explanatory and predictive power. Methods: PubMed was exhaustively searched using the phrase “adenomyosis and animal model”, “adenomyosis and experimental model”, “adenomyosis and mouse”, and “adenomyosis and rat”, and the resultant papers were retrieved, carefully read, and the resultant information distilled. All the retrieved papers were then reviewed in a narrative manner. Results: Among all published animal models of adenomyosis, the mouse model of adenomyosis induced by endometrial–myometrial interface disruption (EMID) seems to satisfy the requirements of falsifiability and has the predictive capability and also Hill’s causality criteria. Other theories only partially satisfy Hill’s criteria of causality. In particular, animal models of adenomyosis induced by hyperestrogenism, hyperprolactinemia, or long-term exposure to progestogens without much epidemiological documentation and adenomyosis is usually not the exclusive uterine pathology consequent to those induction procedures. Regardless, uterine disruption appears to be a necessary but not sufficient condition for causing adenomyosis. Conclusions: EMID is, however, unlikely the sole cause for adenomyosis. Future studies, including animal studies, are warranted to understand how and why in utero and/or prenatal exposure to elevated levels of estrogen or estrogenic compounds increases the risk of developing adenomyosis in adulthood, to elucidate whether prolactin plays any role in its pathogenesis, and to identify sufficient condition(s) that cause adenomyosis.
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18
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Dalal H, Dahlgren M, Gladchuk S, Brueffer C, Gruvberger-Saal SK, Saal LH. Clinical associations of ESR2 (estrogen receptor beta) expression across thousands of primary breast tumors. Sci Rep 2022; 12:4696. [PMID: 35304506 PMCID: PMC8933558 DOI: 10.1038/s41598-022-08210-3] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Accepted: 03/03/2022] [Indexed: 12/31/2022] Open
Abstract
Estrogen receptor alpha (ERα, encoded by ESR1) is a well-characterized transcription factor expressed in more than 75% of breast tumors and is the key biomarker to direct endocrine therapies. On the other hand, much less is known about estrogen receptor beta (ERβ, encoded by ESR2) and its importance in cancer. Previous studies had some disagreement, however most reports suggested a more favorable prognosis for patients with high ESR2 expression. To add further clarity to ESR2 in breast cancer, we interrogated a large population-based cohort of primary breast tumors (n = 3207) from the SCAN-B study. RNA-seq shows ESR2 is expressed at low levels overall with a slight inverse correlation to ESR1 expression (Spearman R = −0.18, p = 2.2e−16), and highest ESR2 expression in the basal- and normal-like PAM50 subtypes. ESR2-high tumors had favorable overall survival (p = 0.006), particularly in subgroups receiving endocrine therapy (p = 0.03) and in triple-negative breast cancer (p = 0.01). These results were generally robust in multivariable analyses accounting for patient age, tumor size, node status, and grade. Gene modules consistent with immune response were associated to ESR2-high tumors. Taken together, our results indicate that ESR2 is generally expressed at low levels in breast cancer but associated with improved overall survival and may be related to immune response modulation.
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Affiliation(s)
- Hina Dalal
- Division of Oncology, Department of Clinical Sciences Lund, Lund University Cancer Center, Lund University, Medicon Village 404-B2, 22381, Lund, Sweden.,Lund University Cancer Center, Medicon Village, Lund, Sweden
| | - Malin Dahlgren
- Division of Oncology, Department of Clinical Sciences Lund, Lund University Cancer Center, Lund University, Medicon Village 404-B2, 22381, Lund, Sweden.,Lund University Cancer Center, Medicon Village, Lund, Sweden
| | - Sergii Gladchuk
- Division of Oncology, Department of Clinical Sciences Lund, Lund University Cancer Center, Lund University, Medicon Village 404-B2, 22381, Lund, Sweden.,Lund University Cancer Center, Medicon Village, Lund, Sweden
| | - Christian Brueffer
- Division of Oncology, Department of Clinical Sciences Lund, Lund University Cancer Center, Lund University, Medicon Village 404-B2, 22381, Lund, Sweden.,Lund University Cancer Center, Medicon Village, Lund, Sweden
| | - Sofia K Gruvberger-Saal
- Division of Oncology, Department of Clinical Sciences Lund, Lund University Cancer Center, Lund University, Medicon Village 404-B2, 22381, Lund, Sweden.,Section for Molecular Diagnostics, Skåne University Hospital, Lund, Sweden
| | - Lao H Saal
- Division of Oncology, Department of Clinical Sciences Lund, Lund University Cancer Center, Lund University, Medicon Village 404-B2, 22381, Lund, Sweden. .,Lund University Cancer Center, Medicon Village, Lund, Sweden.
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19
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Langendonk M, de Jong MRW, Smit N, Seiler J, Reitsma B, Ammatuna E, Glaudemans AWJM, van den Berg A, Huls GA, Visser L, van Meerten T. Identification of the estrogen receptor beta as a possible new tamoxifen-sensitive target in diffuse large B-cell lymphoma. Blood Cancer J 2022; 12:36. [PMID: 35256592 PMCID: PMC8901714 DOI: 10.1038/s41408-022-00631-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 01/21/2022] [Accepted: 01/27/2022] [Indexed: 01/14/2023] Open
Abstract
Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype. Despite the proven efficacy of combined immunochemotherapy (R-CHOP) in the majority of patients, ~40% of DLBCL patients do not respond or will relapse and consequently have a very poor prognosis. The development of targeted therapies has not improved patient survival, underscoring the need for new treatment approaches. Using an unbiased genome-wide CD20 guilt-by-association approach in more than 1800 DLBCL patients, we previously identified the estrogen receptor beta (ERβ) as a new target in DLBCL. Here, we demonstrate that ERβ is expressed at significantly higher levels in DLBCL compared to normal B cells, and ERβ plays a role in the protection against apoptosis in DLBCL. Targeting of the ERβ with the selective estrogen receptor modulator tamoxifen reduces cell viability in all tested DLBCL cell lines. Tamoxifen-induced cell death was significantly decreased in an ERβ knock-out cell line. The activity of tamoxifen was confirmed in a xenograft human lymphoma model, as tumor growth decreased, and survival significantly improved. Finally, tamoxifen-treated breast cancer (BC) patients showed a significantly reduced risk of 38% for DLBCL compared to BC patients who did not receive tamoxifen. Our findings provide a rationale to investigate tamoxifen, a hormonal drug with a good safety profile, in DLBCL patients.
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Affiliation(s)
- Myra Langendonk
- University of Groningen, University Medical Center Groningen, Department of Hematology, Groningen, the Netherlands
| | - Mathilde R W de Jong
- University of Groningen, University Medical Center Groningen, Department of Hematology, Groningen, the Netherlands
| | - Nienke Smit
- University of Groningen, University Medical Center Groningen, Department of Hematology, Groningen, the Netherlands
| | - Jonas Seiler
- University of Groningen, ERIBA, Genomic Instability in Development and Disease, Groningen, the Netherlands
| | - Bart Reitsma
- University of Groningen, University Medical Center Groningen, Department of Hematology, Groningen, the Netherlands
| | - Emanuele Ammatuna
- University of Groningen, University Medical Center Groningen, Department of Hematology, Groningen, the Netherlands
| | - Andor W J M Glaudemans
- University of Groningen, University Medical center Groningen, Department of Nuclear Medicine and Molecular Imaging, Groningen, The Netherlands
| | - Anke van den Berg
- University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, the Netherlands
| | - Gerwin A Huls
- University of Groningen, University Medical Center Groningen, Department of Hematology, Groningen, the Netherlands
| | - Lydia Visser
- University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, the Netherlands
| | - Tom van Meerten
- University of Groningen, University Medical Center Groningen, Department of Hematology, Groningen, the Netherlands.
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20
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Li YZ, Zhang C, Pei JP, Zhang WC, Zhang CD, Dai DQ. The functional role of Pescadillo ribosomal biogenesis factor 1 in cancer. J Cancer 2022; 13:268-277. [PMID: 34976188 PMCID: PMC8692700 DOI: 10.7150/jca.58982] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Accepted: 07/20/2021] [Indexed: 12/13/2022] Open
Abstract
Tumors are neogrowths formed by the growth of normal cells or tissues through complex mechanisms under the influence of many factors. The occurrence and development of tumors are affected by many factors. Pescadillo ribosomal biogenesis factor 1 (PES1) has been identified as a cancer-related gene. The study of these genes may open up new avenues for early diagnosis, treatment and prognosis of tumors. As a nucleolar protein and part of the Pes1/Bop1/WDR12 (PeBoW) complex, PES1 is involved in ribosome biogenesis and DNA replication. Many studies have shown that high expression of PES1 is often closely related to the occurrence, proliferation, invasion, metastasis, prognosis and sensitivity to chemotherapeutics of various human malignant tumors through a series of molecular mechanisms and signaling pathways. The molecules that regulate the expression of PES1 include microRNA (miRNA), circular RNA (circRNA), c-Jun, bromodomain-containing protein 4 (BRD4) and nucleolar phosphoprotein B23. However, the detailed pathogenic mechanisms of PES1 overexpression in human malignancies remains unclear. This article summarizes the role of PES1 in the carcinogenesis, prognosis and treatment of multiple tumors, and introduces the molecular mechanisms and signal transduction pathways related to PES1.
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Affiliation(s)
- Yong-Zhi Li
- Department of Gastrointestinal Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China
| | - Cheng Zhang
- Department of Gastrointestinal Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China
| | - Jun-Peng Pei
- Department of Gastrointestinal Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China
| | - Wan-Chuan Zhang
- Department of Gastrointestinal Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China
| | - Chun-Dong Zhang
- Department of Gastrointestinal Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China.,Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
| | - Dong-Qiu Dai
- Department of Gastrointestinal Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China.,Cancer Center, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China
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21
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Choi Y. Estrogen Receptor β Expression and Its Clinical Implication in Breast Cancers: Favorable or Unfavorable? J Breast Cancer 2022; 25:75-93. [PMID: 35380018 PMCID: PMC9065353 DOI: 10.4048/jbc.2022.25.e9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 11/18/2021] [Accepted: 02/03/2022] [Indexed: 11/30/2022] Open
Abstract
There are two estrogen receptor (ER) genes (ESR1/ERα and ESR2/ERβ) in humans. Of those. ERβ, the second ER isotype identified in 1996, is differentially expressed in different phenotypes and molecular subtypes of breast cancer (BCa), and is highly expressed in ERα-negative BCa and triple-negative BCa (TNBC). This review summarizes the potential clinical relevance of ERβ in BCa and the challenges associated with studies on the role of ERβ in BCa. The experimental and clinical studies evaluating clinical outcomes and associations with clinical characteristics and responses to endocrine therapy on targeting ERβ reviewed herein indicate that ERβ is a clinically important biomarker in BCa. The reviewed studies also suggest that each ERβ isoform has a distinct role in BCa subtypes and the potential of novel- targeted therapies in BCa, especially ERα-negative BCa and TNBC. However, the findings of many studies on ERβ are inconsistent, and the exact role of ERβ in BCa remains elusive; this may potentially be attributed to the complexity of ERβ isoforms, but also to the lack of standardized testing protocol. Thus, successful clinical application of ERβ requires the development of standardized, reproducible, and objective measurement methods for ERβ that can be widely and routinely applied in clinical setting.
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Affiliation(s)
- Young Choi
- Department of Pathology, Yale School of Medicine, Hartsdale, NY, USA
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22
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Maharjan CK, Mo J, Wang L, Kim MC, Wang S, Borcherding N, Vikas P, Zhang W. Natural and Synthetic Estrogens in Chronic Inflammation and Breast Cancer. Cancers (Basel) 2021; 14:cancers14010206. [PMID: 35008370 PMCID: PMC8744660 DOI: 10.3390/cancers14010206] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 12/17/2021] [Accepted: 12/19/2021] [Indexed: 12/17/2022] Open
Abstract
The oncogenic role of estrogen receptor (ER) signaling in breast cancer has long been established. Interaction of estrogen with estrogen receptor (ER) in the nucleus activates genomic pathways of estrogen signaling. In contrast, estrogen interaction with the cell membrane-bound G-protein-coupled estrogen receptor (GPER) activates the rapid receptor-mediated signaling transduction cascades. Aberrant estrogen signaling enhances mammary epithelial cell proliferation, survival, and angiogenesis, hence is an important step towards breast cancer initiation and progression. Meanwhile, a growing number of studies also provide evidence for estrogen's pro- or anti-inflammatory roles. As other articles in this issue cover classic ER and GPER signaling mediated by estrogen, this review will discuss the crucial mechanisms by which estrogen signaling influences chronic inflammation and how that is involved in breast cancer. Xenoestrogens acquired from plant diet or exposure to industrial products constantly interact with and alter innate estrogen signaling at various levels. As such, they can modulate chronic inflammation and breast cancer development. Natural xenoestrogens generally have anti-inflammatory properties, which is consistent with their chemoprotective role in breast cancer. In contrast, synthetic xenoestrogens are proinflammatory and carcinogenic compounds that can increase the risk of breast cancer. This article also highlights important xenoestrogens with a particular focus on their role in inflammation and breast cancer. Improved understanding of the complex relationship between estrogens, inflammation, and breast cancer will guide clinical research on agents that could advance breast cancer prevention and therapy.
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Affiliation(s)
- Chandra K. Maharjan
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA; (C.K.M.); (J.M.); (L.W.); (M.-C.K.)
| | - Jiao Mo
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA; (C.K.M.); (J.M.); (L.W.); (M.-C.K.)
| | - Lei Wang
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA; (C.K.M.); (J.M.); (L.W.); (M.-C.K.)
| | - Myung-Chul Kim
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA; (C.K.M.); (J.M.); (L.W.); (M.-C.K.)
| | - Sameul Wang
- Canyonoak Consulting LLC, San Diego, CA 92127, USA;
| | - Nicholas Borcherding
- Department of Pathology and Immunology, School of Medicine, Washington University, St. Louis, MO 63110, USA;
| | - Praveen Vikas
- Department of Internal Medicine, Carver College of Medicine, Iowa City, IA 52242, USA;
| | - Weizhou Zhang
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA; (C.K.M.); (J.M.); (L.W.); (M.-C.K.)
- Mechanism of Oncogenesis Program, University of Florida Health Cancer Center, University of Florida, Gainesville, FL 32610, USA
- Correspondence: to: ; Tel.: +1-352-273-6748
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23
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Nzegwu MA, Nwokoro O, Nnamani C, Enemuo VC, Nzegwu VI, Nwoye O, Edeh A, Nwankwo K. TP 53 status and estrogen receptor-beta in triple negative breast cancer management in Africa: Time to rethink regime management of triple negative breast cancer and save more lives in Nigeria. Rare Tumors 2021; 13:20363613211050355. [PMID: 34659670 PMCID: PMC8511903 DOI: 10.1177/20363613211050355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Affiliation(s)
| | - Onyekachi Nwokoro
- Department of Morbid Anatomy, University of Nigeria, Nsukka, Nigeria
| | - Christian Nnamani
- Department of Morbid Anatomy, University of Nigeria, Nsukka, Nigeria
| | | | | | - Ogochukwu Nwoye
- Department of Morbid Anatomy, University of Nigeria, Nsukka, Nigeria
| | - Anthony Edeh
- Department of Radiation Medicine, University of Nigeria, Nsukka, Nigeria
| | - Kenneth Nwankwo
- Department of Surgery, Enugu State University of Science and Technology, Enugu, Nigeria
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24
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Akyu Takei R, Tomihara K, Yamazaki M, Moniruzzaman R, Heshiki W, Sekido K, Tachinami H, Sakurai K, Yonesi A, Imaue S, Fujiwara K, Noguchi M. Protumor role of estrogen receptor expression in oral squamous cell carcinoma cells. Oral Surg Oral Med Oral Pathol Oral Radiol 2021; 132:549-565. [PMID: 34518137 DOI: 10.1016/j.oooo.2021.04.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2020] [Revised: 01/26/2021] [Accepted: 04/18/2021] [Indexed: 10/21/2022]
Abstract
OBJECTIVE Accumulating evidence has demonstrated the protumor role of estrogen receptor (ER)-mediated signaling in multiple cancer types, which is distinct from this signaling in sex steroid-dependent organs. However, its role in oral squamous cell carcinoma (OSCC) remains unclear. STUDY DESIGN We assessed the expression of ERα and ERβ in human OSCC tissues by immunohistochemistry and evaluated the expression of both receptors in OSCC cell lines by immunoblotting and flow cytometry. To further assess the contribution of ER-mediated signals to oral cancer progression, proliferation, invasion, and chemosensitivity, cell lines were stimulated with the ER agonist β-estradiol. RESULTS Immunohistochemical analysis of OSCC tissues showed that ERβ was present in the cytoplasm and nuclei of OSCC cells. In contrast, ERα was not detected in any of the cases analyzed. Additionally, the proliferation and invasiveness of OSCC cells were significantly elevated following stimulation with β-estradiol. Chemotherapeutic agent-induced apoptosis of cancer cells was attenuated by pretreatment with β-estradiol. CONCLUSIONS ER-mediated signaling plays a crucial role in oral cancer progression by facilitating the proliferation, invasion, and chemoresistance of OSCC cells, indicating its potential for developing novel targeted therapies for this type of cancer.
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Affiliation(s)
- Rie Akyu Takei
- Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Academic Assembly, University of Toyama, Toyama, Japan; Department of Oral and Maxillofacial Surgery, Saiseikai Toyama Hospital, Toyama, Japan
| | - Kei Tomihara
- Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Academic Assembly, University of Toyama, Toyama, Japan.
| | - Manabu Yamazaki
- Division of Oral Pathology, Department of Tissue Regeneration and Reconstruction, Niigata University, Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Rohan Moniruzzaman
- Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Academic Assembly, University of Toyama, Toyama, Japan
| | - Wataru Heshiki
- Department of Oral and Maxillofacial Surgery, Regional Independent Administrative Corporation Naha City Hospital, Naha, Japan
| | - Katsuhisa Sekido
- Department of Oral and Maxillofacial Surgery, Toyama Red Cross Hospital, Toyama, Japan
| | - Hidetake Tachinami
- Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Academic Assembly, University of Toyama, Toyama, Japan
| | - Kotaro Sakurai
- Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Academic Assembly, University of Toyama, Toyama, Japan
| | - Amirmoezz Yonesi
- Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Academic Assembly, University of Toyama, Toyama, Japan
| | - Shuichi Imaue
- Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Academic Assembly, University of Toyama, Toyama, Japan
| | - Kumiko Fujiwara
- Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Academic Assembly, University of Toyama, Toyama, Japan
| | - Makoto Noguchi
- Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Academic Assembly, University of Toyama, Toyama, Japan
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25
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Karakas B, Aka Y, Giray A, Temel SG, Acikbas U, Basaga H, Gul O, Kutuk O. Mitochondrial estrogen receptors alter mitochondrial priming and response to endocrine therapy in breast cancer cells. Cell Death Discov 2021; 7:189. [PMID: 34294688 PMCID: PMC8298581 DOI: 10.1038/s41420-021-00573-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Revised: 06/04/2021] [Accepted: 07/05/2021] [Indexed: 12/21/2022] Open
Abstract
Breast cancer is the most common cancer with a high rate of mortality and morbidity among women worldwide. Estrogen receptor status is an important prognostic factor and endocrine therapy is the choice of first-line treatment in ER-positive breast cancer. However, most tumors develop resistance to endocrine therapy. Here we demonstrate that BH3 profiling technology, in particular, dynamic BH3 profiling can predict the response to endocrine therapy agents as well as the development of acquired resistance in breast cancer cells independent of estrogen receptor status. Immunofluorescence analysis and subcellular fractionation experiments revealed distinct ER-α and ER-β subcellular localization patterns in breast cancer cells, including mitochondrial localization of both receptor subtypes. shRNA-mediated depletion of ER-β in breast cancer cells led to resistance to endocrine therapy agents and selective reconstitution of ER-β in mitochondria restored sensitivity. Notably, mitochondria-targeted ER-α did not restore sensitivity, even conferred further resistance to endocrine therapy agents. In addition, expressing mitochondria-targeted ER-β in breast cancer cells resulted in decreased mitochondrial respiration alongside increased total ROS and mitochondrial superoxide production. Furthermore, our data demonstrated that mitochondrial ER-β can be successfully targeted by the selective ER-β agonist Erteberel. Thus, our findings provide novel findings on mitochondrial estrogen signaling in breast cancer cells and suggest the implementation of the dynamic BH3 technique as a tool to predict acquired endocrine therapy resistance.
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Affiliation(s)
- Bahriye Karakas
- Sabanci University, Molecular Biology, Genetics and Bioengineering Program, Istanbul, Turkey
| | - Yeliz Aka
- Baskent University School of Medicine, Dept. of Immunology, Adana Dr. Turgut Noyan Medical and Research Center, Adana, Turkey
| | - Asli Giray
- Department of Genetics and Bioengineering, Alanya Alaaddin Keykubat University, Alanya, Turkey
| | - Sehime Gulsun Temel
- Bursa Uludag University, Faculty of Medicine, Department of Histology and Embryology, Bursa, Turkey
- Bursa Uludag University, Faculty of Medicine, Department of Medical Genetics, Bursa, Turkey
- Bursa Uludag University, Institute of Health Sciences, Department of Translational Medicine, Bursa, Turkey
| | - Ufuk Acikbas
- Baskent University School of Medicine, Dept. of Immunology, Adana Dr. Turgut Noyan Medical and Research Center, Adana, Turkey
| | - Huveyda Basaga
- Sabanci University, Molecular Biology, Genetics and Bioengineering Program, Istanbul, Turkey
| | - Ozgur Gul
- Bilgi University, Department of Genetics and Bioengineering, Istanbul, Turkey
| | - Ozgur Kutuk
- Baskent University School of Medicine, Dept. of Immunology, Adana Dr. Turgut Noyan Medical and Research Center, Adana, Turkey.
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26
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Carcinogenesis of Triple-Negative Breast Cancer and Sex Steroid Hormones. Cancers (Basel) 2021; 13:cancers13112588. [PMID: 34070471 PMCID: PMC8197527 DOI: 10.3390/cancers13112588] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 05/19/2021] [Accepted: 05/23/2021] [Indexed: 11/21/2022] Open
Abstract
Simple Summary Triple-negative breast cancer (TNBC) lacks all of three treatment targets (estrogen receptor-α, ER-α; progesterone receptor, PgR; and human epidermal growth factor receptor 2, HER2) and is usually associated with a poor clinical outcome; however, several sex steroid receptors, such as androgen receptor (AR), ER-β, and G-protein-coupled estrogen receptor, are frequently expressed and their biological and clinical importance has been suggested. Despite the structural similarity between sex steroid hormones (androgens and estrogens) or receptors (AR and ER-β), similar signaling mechanisms of these hormones, and the coexistence of these hormones and their receptors in TNBC in a clinical setting, most studies or reviews focused on only one of these receptors, and rarely reviewed them in a comprehensive way. In this review, the carcinogenic or pathobiological role of sex steroid hormones in TNBC is considered, focusing on common and differing features of hormone actions. Abstract Triple-negative breast cancer (TNBC) lacks an effective treatment target and is usually associated with a poor clinical outcome; however, hormone unresponsiveness, which is the most important biological characteristic of TNBC, only means the lack of nuclear estrogenic signaling through the classical estrogen receptor (ER), ER-α. Several sex steroid receptors other than ER-α: androgen receptor (AR), second ER, ER-β, and non-nuclear receptors represented by G-protein-coupled estrogen receptor (GPER), are frequently expressed in TNBC and their biological and clinical importance has been suggested by a large number of studies. Despite the structural similarity between each sex steroid hormone (androgens and estrogens) or each receptor (AR and ER-β), and similarity in the signaling mechanisms of these hormones, most studies or reviews focused on one of these receptors, and rarely reviewed them in a comprehensive way. Considering the coexistence of these hormones and their receptors in TNBC in a clinical setting, a comprehensive viewpoint would be important to correctly understand the association between the carcinogenic mechanism or pathobiology of TNBC and sex steroid hormones. In this review, the carcinogenic or pathobiological role of sex steroid hormones in TNBC is considered, focusing on the common and divergent features of the action of these hormones.
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27
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van Barele M, Heemskerk-Gerritsen BAM, Louwers YV, Vastbinder MB, Martens JWM, Hooning MJ, Jager A. Estrogens and Progestogens in Triple Negative Breast Cancer: Do They Harm? Cancers (Basel) 2021; 13:2506. [PMID: 34063736 PMCID: PMC8196589 DOI: 10.3390/cancers13112506] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 04/29/2021] [Accepted: 05/17/2021] [Indexed: 12/31/2022] Open
Abstract
Triple-negative breast cancers (TNBC) occur more frequently in younger women and do not express estrogen receptor (ER) nor progesterone receptor (PR), and are therefore often considered hormone-insensitive. Treatment of premenopausal TNBC patients almost always includes chemotherapy, which may lead to premature ovarian insufficiency (POI) and can severely impact quality of life. Hormone replacement therapy (HRT) is contraindicated for patients with a history of hormone-sensitive breast cancer, but the data on safety for TNBC patients is inconclusive, with a few randomized trials showing increased risk-ratios with wide confidence intervals for recurrence after HRT. Here, we review the literature on alternative pathways from the classical ER/PR. We find that for both estrogens and progestogens, potential alternatives exist for exerting their effects on TNBC, ranging from receptor conversion, to alternative receptors capable of binding estrogens, as well as paracrine pathways, such as RANK/RANKL, which can cause progestogens to indirectly stimulate growth and metastasis of TNBC. Finally, HRT may also influence other hormones, such as androgens, and their effects on TNBCs expressing androgen receptors (AR). Concluding, the assumption that TNBC is completely hormone-insensitive is incorrect. However, the direction of the effects of the alternative pathways is not always clear, and will need to be investigated further.
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Affiliation(s)
- Mark van Barele
- Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Centre, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands; (M.v.B.); (B.A.M.H.-G.); (J.W.M.M.); (M.J.H.)
| | - Bernadette A. M. Heemskerk-Gerritsen
- Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Centre, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands; (M.v.B.); (B.A.M.H.-G.); (J.W.M.M.); (M.J.H.)
| | - Yvonne V. Louwers
- Department of Obstetrics and Gynaecology, Erasmus MC, University Medical Centre, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands;
| | - Mijntje B. Vastbinder
- Department of Internal Medicine, Ijsselland Hospital, Prins Constantijnweg 2, 2906 ZC Capelle aan den IJssel, The Netherlands;
| | - John W. M. Martens
- Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Centre, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands; (M.v.B.); (B.A.M.H.-G.); (J.W.M.M.); (M.J.H.)
| | - Maartje J. Hooning
- Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Centre, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands; (M.v.B.); (B.A.M.H.-G.); (J.W.M.M.); (M.J.H.)
| | - Agnes Jager
- Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Centre, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands; (M.v.B.); (B.A.M.H.-G.); (J.W.M.M.); (M.J.H.)
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28
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Božović A, Mandušić V, Todorović L, Krajnović M. Estrogen Receptor Beta: The Promising Biomarker and Potential Target in Metastases. Int J Mol Sci 2021; 22:ijms22041656. [PMID: 33562134 PMCID: PMC7914503 DOI: 10.3390/ijms22041656] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 12/24/2020] [Accepted: 01/15/2021] [Indexed: 12/21/2022] Open
Abstract
The discovery of the Estrogen Receptor Beta (ERβ) in 1996 opened new perspectives in the diagnostics and therapy of different types of cancer. Here, we present a review of the present research knowledge about its role in endocrine-related cancers: breast, prostate, and thyroid, and colorectal cancers. We also discuss the reasons for the controversy of its role in carcinogenesis and why it is still not in use as a biomarker in clinical practice. Given that the diagnostics and therapy would benefit from the introduction of new biomarkers, we suggest ways to overcome the contradictions in elucidating the role of ERβ.
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29
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Arana Echarri A, Beresford M, Campbell JP, Jones RH, Butler R, Gollob KJ, Brum PC, Thompson D, Turner JE. A Phenomic Perspective on Factors Influencing Breast Cancer Treatment: Integrating Aging and Lifestyle in Blood and Tissue Biomarker Profiling. Front Immunol 2021; 11:616188. [PMID: 33597950 PMCID: PMC7882710 DOI: 10.3389/fimmu.2020.616188] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2020] [Accepted: 12/11/2020] [Indexed: 01/10/2023] Open
Abstract
Breast cancer is the most common malignancy among women worldwide. Over the last four decades, diagnostic and therapeutic procedures have improved substantially, giving patients with localized disease a better chance of cure, and those with more advanced cancer, longer periods of disease control and survival. However, understanding and managing heterogeneity in the clinical response exhibited by patients remains a challenge. For some treatments, biomarkers are available to inform therapeutic options, assess pathological response and predict clinical outcomes. Nevertheless, some measurements are not employed universally and lack sensitivity and specificity, which might be influenced by tissue-specific alterations associated with aging and lifestyle. The first part of this article summarizes available and emerging biomarkers for clinical use, such as measurements that can be made in tumor biopsies or blood samples, including so-called liquid biopsies. The second part of this article outlines underappreciated factors that could influence the interpretation of these clinical measurements and affect treatment outcomes. For example, it has been shown that both adiposity and physical activity can modify the characteristics of tumors and surrounding tissues. In addition, evidence shows that inflammaging and immunosenescence interact with treatment and clinical outcomes and could be considered prognostic and predictive factors independently. In summary, changes to blood and tissues that reflect aging and patient characteristics, including lifestyle, are not commonly considered clinically or in research, either for practical reasons or because the supporting evidence base is developing. Thus, an aim of this article is to encourage an integrative phenomic approach in oncology research and clinical management.
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Affiliation(s)
| | - Mark Beresford
- Department of Oncology and Haematology, Royal United Hospitals Bath NHS Trust, Bath, United Kingdom
| | | | - Robert H. Jones
- Department of Medical Oncology, Velindre Cancer Centre, Cardiff, United Kingdom
- Department of Cancer and Genetics, Cardiff University, Cardiff, United Kingdom
| | - Rachel Butler
- South West Genomics Laboratory Hub, North Bristol NHS Trust, Bristol, United Kingdom
| | - Kenneth J. Gollob
- International Center for Research, A.C.Camargo Cancer Center, São Paulo, Brazil
| | - Patricia C. Brum
- School of Physical Education and Sport, University of São Paulo, São Paulo, Brazil
| | - Dylan Thompson
- Department for Health, University of Bath, Bath, United Kingdom
| | - James E. Turner
- Department for Health, University of Bath, Bath, United Kingdom
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30
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Pather K, Augustine TN. Tamoxifen induces hypercoagulation and alterations in ERα and ERβ dependent on breast cancer sub-phenotype ex vivo. Sci Rep 2020; 10:19256. [PMID: 33159119 PMCID: PMC7648622 DOI: 10.1038/s41598-020-75779-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Accepted: 09/23/2020] [Indexed: 12/24/2022] Open
Abstract
Tamoxifen shows efficacy in reducing breast cancer-related mortality but clinically, is associated with increased risk for thromboembolic events. We aimed to determine whether breast tumour sub-phenotype could predict propensity for thrombosis. We present two ex vivo Models of Tamoxifen-therapy, Model 1 in which treatment recapitulates accumulation within breast tissue, by treating MCF7 and T47D cells directly prior to exposure to blood constituents; and Model 2 in which we recreate circulating Tamoxifen by treating blood constituents prior to exposure to cancer cells. Blood constituents included whole blood, platelet-rich plasma and platelet-poor plasma. Hypercoagulation was assessed as a function of thrombin activity, expression of CD62P and CD63 activation markers defined as an index of platelet activation, and platelet morphology; while oestrogen receptor expression was assessed using immunocytochemistry with quantitative analysis. We determined, in concert with clinical studies and contrary to selected laboratory investigations, that Tamoxifen induces hypercoagulation, dependent on sub-phenotypes, with the T47D cell line capacity most enhanced. We determined a weak positive correlation between oestrogen receptor expression, and CD62P and CD63; indicating an association between tumour invasion profiles and hypercoagulation, however, other yet unknown factors may play a predictive role in defining hypercoagulation.
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Affiliation(s)
- K Pather
- School of Anatomical Sciences, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, Johannesburg, 2193, South Africa.
| | - T N Augustine
- School of Anatomical Sciences, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, Johannesburg, 2193, South Africa.
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31
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Treeck O, Schüler-Toprak S, Ortmann O. Estrogen Actions in Triple-Negative Breast Cancer. Cells 2020; 9:cells9112358. [PMID: 33114740 PMCID: PMC7692567 DOI: 10.3390/cells9112358] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 10/15/2020] [Accepted: 10/21/2020] [Indexed: 12/11/2022] Open
Abstract
Triple-negative breast cancer (TNBC) lacks estrogen receptor (ER) α, but the expression of estrogen receptors ERβ and G protein-coupled estrogen receptor 1 (GPER-1) is able to trigger estrogen-responsivity in TNBC. Estrogen signaling in TNBC can also be activated and modulated by the constitutively active estrogen-related receptors (ERRs). In this review article, we discuss the role of ERβ and GPER-1 as mediators of E2 action in TNBC as well as the function of ERRs as activators and modulators of estrogen signaling in this cancer entity. For this purpose, original research articles on estrogen actions in TNBC were considered, which are listed in the PubMed database. Additionally, we performed meta-analyses of publicly accessible integrated gene expression and survival data to elucidate the association of ERβ, GPER-1, and ERR expression levels in TNBC with survival. Finally, options for endocrine therapy strategies for TNBC were discussed.
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Hatono M, Ikeda H, Suzuki Y, Kajiwara Y, Kawada K, Tsukioki T, Kochi M, Suzawa K, Iwamoto T, Yamamoto H, Shien T, Yamane M, Taira N, Doihara H, Toyooka S. Effect of isoflavones on breast cancer cell development and their impact on breast cancer treatments. Breast Cancer Res Treat 2020; 185:307-316. [PMID: 33034801 DOI: 10.1007/s10549-020-05957-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 09/28/2020] [Indexed: 10/23/2022]
Abstract
PURPOSE Epidemiological studies have suggested that intake of soy isoflavones is associated with a reduced risk of development of breast cancer and an improved prognosis in patients with breast cancer. In addition, basic research has demonstrated the antitumor effects of these compounds on breast cancer cell lines. However, the detailed effects of the intake of equol, which is one of the metabolites of the soy isoflavones, are yet to be clarified on the risk of development and recurrence of breast cancer and its interactions with drugs used for treating breast cancer. This study aimed to determine the antitumor effects of equol and investigate the impact of adding equol to therapeutic agents for breast cancer using breast cancer cell lines. METHODS We examined the antitumor effect of equol on breast cancer cell lines using MTS assay. We also studied the combined effect of equol and the existing hormonal or chemotherapeutic agents using combination index. We evaluated the expressions of the related proteins by Western blot analysis and correlated the findings with the antitumor effect. RESULTS Equol showed bi-phasic protumor and antitumor effects; at a low concentration, it promoted the tumor growth in hormone receptor-positive cell lines, whereas antitumor effects were generally observed when an excessive amount of dose unexpected in the blood and the tissue was administered. When used with tamoxifen, equol might have some antagonistic effect, although it depends on equol concentration and the type of cancer cells. CONCLUSIONS We confirmed that equol has dual action, specifically a tumor growth-promoting effect and an antitumor effect. Although the results suggested that equol might exert an antagonistic effect against tamoxifen depending on the concentration, equol did not exert an antagonistic effect on other therapeutic agents.
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Affiliation(s)
- Minami Hatono
- Department of General Thoracic Surgery and Breast and Endocrine Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Hirokuni Ikeda
- Department of General Thoracic Surgery and Breast and Endocrine Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan.
| | - Yoko Suzuki
- Department of General Thoracic Surgery and Breast and Endocrine Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Yukiko Kajiwara
- Department of General Thoracic Surgery and Breast and Endocrine Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Kengo Kawada
- Department of General Thoracic Surgery and Breast and Endocrine Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Takahiro Tsukioki
- Department of General Thoracic Surgery and Breast and Endocrine Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Mariko Kochi
- Department of General Thoracic Surgery and Breast and Endocrine Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Ken Suzawa
- Department of General Thoracic Surgery and Breast and Endocrine Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Takayuki Iwamoto
- Department of General Thoracic Surgery and Breast and Endocrine Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Hiromasa Yamamoto
- Department of General Thoracic Surgery and Breast and Endocrine Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Tadahiko Shien
- Department of General Thoracic Surgery and Breast and Endocrine Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Masaomi Yamane
- Department of General Thoracic Surgery and Breast and Endocrine Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Naruto Taira
- Department of General Thoracic Surgery and Breast and Endocrine Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Hiroyoshi Doihara
- Department of General Thoracic Surgery and Breast and Endocrine Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Shinichi Toyooka
- Department of General Thoracic Surgery and Breast and Endocrine Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
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Triggering a switch from basal- to luminal-like breast cancer subtype by the small-molecule diptoindonesin G via induction of GABARAPL1. Cell Death Dis 2020; 11:635. [PMID: 32801338 PMCID: PMC7429843 DOI: 10.1038/s41419-020-02878-z] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 07/28/2020] [Accepted: 08/03/2020] [Indexed: 12/13/2022]
Abstract
Breast cancer is a heterogeneous disease that includes different molecular subtypes. The basal-like subtype has a poor prognosis and a high recurrence rate, whereas the luminal-like subtype confers a more favorable patient prognosis partially due to anti-hormone therapy responsiveness. Here, we demonstrate that diptoindonesin G (Dip G), a natural product, exhibits robust differentiation-inducing activity in basal-like breast cancer cell lines and animal models. Specifically, Dip G treatment caused a partial transcriptome shift from basal to luminal gene expression signatures and prompted sensitization of basal-like breast tumors to tamoxifen therapy. Dip G upregulated the expression of both GABARAPL1 (GABAA receptor-associated protein-like 1) and ERβ. We revealed a previously unappreciated role of GABARAPL1 as a regulator in the specification of breast cancer subtypes that is dependent on ERβ levels. Our findings shed light on new therapeutic opportunities for basal-like breast cancer via a phenotype switch and indicate that Dip G may serve as a leading compound for the therapy of basal-like breast cancer.
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Sellitto A, D’Agostino Y, Alexandrova E, Lamberti J, Pecoraro G, Memoli D, Rocco D, Coviello E, Giurato G, Nassa G, Tarallo R, Weisz A, Rizzo F. Insights into the Role of Estrogen Receptor β in Triple-Negative Breast Cancer. Cancers (Basel) 2020; 12:cancers12061477. [PMID: 32516978 PMCID: PMC7353068 DOI: 10.3390/cancers12061477] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Revised: 06/01/2020] [Accepted: 06/03/2020] [Indexed: 12/12/2022] Open
Abstract
Estrogen receptors (ERα and ERβ) are ligand-activated transcription factors that play different roles in gene regulation and show both overlapping and specific tissue distribution patterns. ERβ, contrary to the oncogenic ERα, has been shown to act as an oncosuppressor in several instances. However, while the tumor-promoting actions of ERα are well-known, the exact role of ERβ in carcinogenesis and tumor progression is not yet fully understood. Indeed, to date, highly variable and even opposite effects have been ascribed to ERβ in cancer, including for example both proliferative and growth-inhibitory actions. Recently ERβ has been proposed as a potential target for cancer therapy, since it is expressed in a variety of breast cancers (BCs), including triple-negative ones (TNBCs). Because of the dependence of TNBCs on active cellular signaling, numerous studies have attempted to unravel the mechanism(s) behind ERβ-regulated gene expression programs but the scenario has not been fully revealed. We comprehensively reviewed the current state of knowledge concerning ERβ role in TNBC biology, focusing on the different signaling pathways and cellular processes regulated by this transcription factor, as they could be useful in identifying new diagnostic and therapeutic approaches for TNBC.
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Affiliation(s)
- Assunta Sellitto
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Italy; (A.S.); (Y.D.); (E.A.); (J.L.); (G.P.); (D.M.); (D.R.); (G.G.); (G.N.); (R.T.)
| | - Ylenia D’Agostino
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Italy; (A.S.); (Y.D.); (E.A.); (J.L.); (G.P.); (D.M.); (D.R.); (G.G.); (G.N.); (R.T.)
| | - Elena Alexandrova
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Italy; (A.S.); (Y.D.); (E.A.); (J.L.); (G.P.); (D.M.); (D.R.); (G.G.); (G.N.); (R.T.)
| | - Jessica Lamberti
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Italy; (A.S.); (Y.D.); (E.A.); (J.L.); (G.P.); (D.M.); (D.R.); (G.G.); (G.N.); (R.T.)
| | - Giovanni Pecoraro
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Italy; (A.S.); (Y.D.); (E.A.); (J.L.); (G.P.); (D.M.); (D.R.); (G.G.); (G.N.); (R.T.)
| | - Domenico Memoli
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Italy; (A.S.); (Y.D.); (E.A.); (J.L.); (G.P.); (D.M.); (D.R.); (G.G.); (G.N.); (R.T.)
| | - Domenico Rocco
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Italy; (A.S.); (Y.D.); (E.A.); (J.L.); (G.P.); (D.M.); (D.R.); (G.G.); (G.N.); (R.T.)
| | - Elena Coviello
- Genomix4Life, via S. Allende 43/L, 84081 Baronissi (SA), Italy;
| | - Giorgio Giurato
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Italy; (A.S.); (Y.D.); (E.A.); (J.L.); (G.P.); (D.M.); (D.R.); (G.G.); (G.N.); (R.T.)
| | - Giovanni Nassa
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Italy; (A.S.); (Y.D.); (E.A.); (J.L.); (G.P.); (D.M.); (D.R.); (G.G.); (G.N.); (R.T.)
| | - Roberta Tarallo
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Italy; (A.S.); (Y.D.); (E.A.); (J.L.); (G.P.); (D.M.); (D.R.); (G.G.); (G.N.); (R.T.)
| | - Alessandro Weisz
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Italy; (A.S.); (Y.D.); (E.A.); (J.L.); (G.P.); (D.M.); (D.R.); (G.G.); (G.N.); (R.T.)
- CRGS (Genome Research Center for Health), University of Salerno Campus of Medicine, 84081 Baronissi (SA), Italy
- Correspondence: (A.W.); (F.R.); Tel.: (39+)-089-965043 (A.W.); Tel.: (39+)-089-965221 (F.R.)
| | - Francesca Rizzo
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Italy; (A.S.); (Y.D.); (E.A.); (J.L.); (G.P.); (D.M.); (D.R.); (G.G.); (G.N.); (R.T.)
- CRGS (Genome Research Center for Health), University of Salerno Campus of Medicine, 84081 Baronissi (SA), Italy
- Correspondence: (A.W.); (F.R.); Tel.: (39+)-089-965043 (A.W.); Tel.: (39+)-089-965221 (F.R.)
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Badve SS, Gökmen-Polar Y. TP53 Status and Estrogen Receptor-Beta in Triple-Negative Breast Cancer: Company Matters. J Natl Cancer Inst 2020; 111:1118-1119. [PMID: 30989234 DOI: 10.1093/jnci/djz052] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Accepted: 04/05/2019] [Indexed: 01/21/2023] Open
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Treeck O, Schüler-Toprak S, Skrzypczak M, Weber F, Ortmann O. Knockdown of PTEN decreases expression of estrogen receptor β and tamoxifen sensitivity of human breast cancer cells. Steroids 2020; 153:108521. [PMID: 31604073 DOI: 10.1016/j.steroids.2019.108521] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Revised: 07/23/2019] [Accepted: 10/01/2019] [Indexed: 01/22/2023]
Abstract
Estrogen receptors (ERs) and the PTEN-Akt-mTor pathway are important growth regulators in human breast cancer cells, which both are known to affect response to tamoxifen therapy. Recently it was reported that ERβ activates PTEN expression and tamoxifen sensitivity of human breast cancer cells. In this study we examined whether expression of ERβ in turn might be affected by tumor suppressor PTEN, analyzed the effect of this interaction on tamoxifen response and the co-expression of both genes in human breast cancer samples. After siRNA-mediated PTEN knockdown, Western blot analysis revealed a reduction of ERβ protein expression by 67.2% in MCF-7 cells and by 73.6% in T-47D cells (both p < 0.01), results which could be verified on the mRNA level. In cells with normal PTEN and ERβ status, after 6 days of treatment with 1 µM 4-OH tamoxifen, E2-driven proliferation was decreased by 64.5% in MCF-7 and by 57.7% in T-47D cells (both p < 0.01). After knockdown of PTEN expression, the same concentration of 4-OH TAM reduced E2-triggered growth only by 34.9% (MCF-7) and by 41.8% (T-47D) (both p < 0.01 vs control siRNA). Importantly, treatment with ERβ agonist DPN (5 nM) significantly decreased the inhibitory effect of a PTEN knockdown on tamoxifen response of both cell lines (p < 0.05). Additionally, Spearmańs rank association analysis of PTEN and ERβ 1 mRNA levels in 115 normal and malignant breast tissue samples revealed a strong positive correlation of both genes (rho = 0.6085, p < 0.0001). The data of previous studies reporting an important role of ERβ in tamoxifen sensitivity and our findings suggest down-regulation of ERβ triggered by PTEN knockdown contributed to the decreased response of breast cancer cells to tamoxifen observed in this study. Our data also suggest expression of ERβ might be maintained by tumor suppressor PTEN in human breast cancer cells.
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Affiliation(s)
- Oliver Treeck
- Department of Obstetrics and Gynecology, University Medical Center Regensburg, Regensburg, Germany.
| | - Susanne Schüler-Toprak
- Department of Obstetrics and Gynecology, University Medical Center Regensburg, Regensburg, Germany
| | - Maciej Skrzypczak
- Second Department of Gynecology, Medical University of Lublin, Lublin, Poland
| | - Florian Weber
- Department of Pathology, University Medical Center Regensburg, Regensburg, Germany
| | - Olaf Ortmann
- Department of Obstetrics and Gynecology, University Medical Center Regensburg, Regensburg, Germany
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Splicing regulatory factors in breast cancer hallmarks and disease progression. Oncotarget 2019; 10:6021-6037. [PMID: 31666932 PMCID: PMC6800274 DOI: 10.18632/oncotarget.27215] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Accepted: 08/29/2019] [Indexed: 12/31/2022] Open
Abstract
By regulating transcript isoform expression levels, alternative splicing provides an additional layer of protein control. Recent studies show evidence that cancer cells use different splicing events to fulfill their requirements in order to develop, progress and metastasize. However, there has been less attention for the role of the complex catalyzing the complicated multistep splicing reaction: the spliceosome. The spliceosome consists of multiple sub-complexes in total comprising 244 proteins or splice factors and 5 associated RNA molecules. Here we discuss the role of splice factors in the oncogenic processes tumors cells need to fulfill their oncogenic properties (the so-called the hallmarks of cancer). Despite the fact that splice factors have been investigated only recently, they seem to play a prominent role in already five hallmarks of cancer: angiogenesis, resisting cell death, sustaining proliferation, deregulating cellular energetics and invasion and metastasis formation by affecting major signaling pathways such as epithelial-to-mesenchymal transition, the Warburg effect, DNA damage response and hormone receptor dependent proliferation. Moreover, we could relate expression of representative genes of four other hallmarks (enabling replicative mortality, genomic instability, avoiding immune destruction and evading growth suppression) to splice factor levels in human breast cancer tumors, suggesting that also these hallmarks could be regulated by splice factors. Since many splice factors are involved in multiple hallmarks of cancer, inhibiting splice factors might provide a new layer of oncogenic control and a powerful method to combat breast cancer progression.
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Heitz F, Kümmel S, Lederer B, Solbach C, Engels K, Ataseven B, Sinn B, Blohmer JU, Denkert C, Barinoff J, Fisseler-Eckhoff A, Loibl S. Impact of Nuclear Oestrogen Receptor Beta Expression in Breast Cancer Patients Undergoing Neoadjuvant Chemotherapy. Geburtshilfe Frauenheilkd 2019; 79:1110-1117. [PMID: 31656321 PMCID: PMC6805199 DOI: 10.1055/a-0987-9898] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2019] [Revised: 07/16/2019] [Accepted: 07/31/2019] [Indexed: 12/31/2022] Open
Abstract
Introduction Oestrogen receptor beta (ER-β) is abundantly expressed in breast cancer (BC), but its impact on neoadjuvant chemotherapy outcome is unknown. Patients and Methods Patients treated in the neoadjuvant GeparTrio trial with available tissue for immunohistochemical analyses were included. Nuclear ER-β expression was correlated with clinico-pathologic characteristics. The impact of its expression on pathological complete response (pCR [ypT0/ypN0]) and survival was determined. Results Samples of 570 patients were available. Low nuclear ER-β expression (IRS < 9) was observed in 48.4% of hormone receptor positive and 58.6% of hormone receptor negative tumours. Low nuclear ER-β expression was associated with higher pCR rates compared to high nuclear ER-β expression (16.1% vs. 4.7%, p = 0.026). Low ER-β expression was no independent predictor of pCR in multivariate analyses. Disease-free and overall survival were not statistically different between patients with high and low nuclear ER-β expression. Triple-negative BCs showed low nuclear ER-β expression in 57.7%, and pCR rates were 27.1% and 0% (p = 0.23) in low and high ER-β expressing tumours, respectively. Conclusion Low ER-β expression is associated with improved pCR rates in univariate analyses. However multivariate analyses and survival analyses do not indicate an impact of ER-β on survival in patients undergoing neoadjuvant chemotherapy. Further examination of ER-β as predictor for endocrine therapy might be of value.
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Affiliation(s)
- Florian Heitz
- Department of Gynaecology and Gynaecologic Oncology, Kliniken Essen-Mitte, Evangelische Huyssens-Stiftung, Essen, Germany
- Department of Gynaecology and Gynaecologic Oncology, Charité University, Berlin, Germany
| | - Sherko Kümmel
- Breast Unit, Kliniken Essen-Mitte, Evangelische Huyssens-Stiftung, Essen, Germany
| | | | - Christine Solbach
- Department of Gynaecology and Obstetrics, Goethe University, Frankfurt, Germany
| | - Knut Engels
- Center for Pathology, Cytology and Molecular Pathology, Neuss, Germany
| | - Beyhan Ataseven
- Department of Gynaecology and Gynaecologic Oncology, Kliniken Essen-Mitte, Evangelische Huyssens-Stiftung, Essen, Germany
- Department of Obstetrics and Gynaecology, University Hospital, LMU München, München, Germany
| | - Bruno Sinn
- Institute of Pathology, Charité University, Berlin, Germany
- German Cancer Consortium (DKTK), Berlin, Germany
| | - Jens Uwe Blohmer
- Department of Gynaecology and Gynaecologic Oncology, Charité University, Berlin, Germany
| | - Carsten Denkert
- Institute of Pathology, Charité University, Berlin, Germany
- German Cancer Consortium (DKTK), Berlin, Germany
- Institut für Pathologie, UKGM – Universitätsklinikum Marburg, Philipps-Universität Marburg, Marburg, Germany
| | - Jana Barinoff
- Department of Gynaecology and Gynaecologic Oncology, Charité University, Berlin, Germany
| | | | - Sibylle Loibl
- German Breast Group (GBG), Neu-Isenburg, Germany
- Senologic Oncology, Düsseldorf, Germany
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Hawse JR, Carter JM, Aspros KGM, Bruinsma ES, Koepplin JW, Negron V, Subramaniam M, Ingle JN, Rech KL, Goetz MP. Optimized immunohistochemical detection of estrogen receptor beta using two validated monoclonal antibodies confirms its expression in normal and malignant breast tissues. Breast Cancer Res Treat 2019; 179:241-249. [PMID: 31571071 DOI: 10.1007/s10549-019-05441-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Accepted: 09/06/2019] [Indexed: 02/07/2023]
Abstract
PURPOSE Significant controversy exists regarding the expression patterns of estrogen receptor beta (ERβ) in normal and diseased breast tissue. To address this issue, we have validated two ERβ antibodies, optimized the IHC protocols for both antibodies and now report the expression patterns of ERβ in normal and malignant breast tissues. METHODS ERβ antibody specificity was determined using western blot and IHC analysis. ERβ protein expression patterns were assessed via IHC in normal breast tissue and invasive breast carcinoma. Further, we report the detailed protocol of the ERβ IHC assay developed in our CAP/CLIA certified laboratory to provide a standardized method for future studies. RESULTS We have confirmed the specificity of two independent ERβ monoclonal antibodies, one that detects total (i.e., full length plus splice variants 2-5, which do not include the ligand binding domain) ERβ protein (PPZ0506) and one that detects only the full-length form, which includes the ligand binding domain, of ERβ (PPG5/10). Using these two antibodies, we demonstrate that ERβ is highly expressed in normal human breast tissue as well as in 20-30% of invasive breast cancers. Further, these two antibodies exhibited similar staining patterns across multiple different tissues and were highly concordant with regard to determining ERβ positivity in breast cancers. CONCLUSIONS ERβ protein was shown to be abundant in the majority of normal breast epithelial cells and is present in 20-30% of breast cancers. Use of these two antibodies, along with their standardized IHC protocols, provide a reference for future studies aimed at determining the utility of ERβ as a prognostic and/or predictive biomarker in various tissues of benign or malignant states.
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Affiliation(s)
- John R Hawse
- Department of Biochemistry and Molecular Biology, Mayo Clinic, 13-21B Guggenheim Building, 200 First St. SW, Rochester, MN, 55905, USA.
| | - Jodi M Carter
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Kirsten G M Aspros
- Department of Biochemistry and Molecular Biology, Mayo Clinic, 13-21B Guggenheim Building, 200 First St. SW, Rochester, MN, 55905, USA
| | - Elizabeth S Bruinsma
- Department of Biochemistry and Molecular Biology, Mayo Clinic, 13-21B Guggenheim Building, 200 First St. SW, Rochester, MN, 55905, USA
| | - Justin W Koepplin
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Vivian Negron
- Department of Pathology, Mayo Clinic, Rochester, MN, USA
| | - Malayannan Subramaniam
- Department of Biochemistry and Molecular Biology, Mayo Clinic, 13-21B Guggenheim Building, 200 First St. SW, Rochester, MN, 55905, USA
| | - James N Ingle
- Department of Oncology, Mayo Clinic, Rochester, MN, USA
| | - Karen L Rech
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Matthew P Goetz
- Department of Oncology, Mayo Clinic, Rochester, MN, USA
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA
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Goto Y, Thike AA, Ong CCH, Lim JX, Md Nasir ND, Li H, Koh VCY, Chen XY, Yeong JPS, Sasano H, Tan PH. Characteristics, behaviour and role of biomarkers in metastatic triple-negative breast cancer. J Clin Pathol 2019; 73:147-153. [PMID: 31563883 DOI: 10.1136/jclinpath-2019-206078] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Revised: 09/04/2019] [Accepted: 09/15/2019] [Indexed: 12/24/2022]
Abstract
AIMS Characterising the factors responsible for metastatic triple-negative breast cancer (TNBC) is of significant importance, considering its high mortality rate and scant data. In this study, we evaluated the characteristics, clinical behaviour and role of biomarkers (androgen receptor (AR), oestrogen receptor beta (ERβ) and p53) in metastatic TNBC. METHODS Immunohistochemistry was performed for AR, ERβ and p53 on 125 primary TNBCs with known metastasis and correlated with clinicopathological parameters and outcome. AR and p53 mRNA profiling was also carried out on 34 tumours from the same series and correlated with outcomes. RESULTS In this cohort, grade 3 and pT2 tumours predominated. The most common site for metastasis was the lung and pleura (41, 32.8%), and 15 (12.0%) cases demonstrated metastasis in multiple sites. Among these, 92% of tumours metastasised without preceding local recurrences. Five- and ten-year overall survival (OS) rates were 27% and 7.2%, while 5- and 10- year survival rates after metastasis were 9.6% and 3.2% respectively. AR, ERβ and p53 protein expressions were observed in 16%, 96.8% and 58.1% of tumours, respectively. A combinational phenotype of AR-ERβ+p53+ tumours was associated with poorer OS (HR 1.543, 95%CI 1.030 to 2.310, p=0.035). Higher AR mRNA levels were significantly associated with favourable OS (p=0.015) and survival after metastasis (p=0.027). CONCLUSIONS Metastatic TNBC harboured aggressive behaviour and displayed predominantly visceral metastasis with most metastatic events occurring without intervening local recurrences. A combinational phenotype of AR-ERβ+p53+ was significantly associated with poorer OS.
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Affiliation(s)
- Yutaro Goto
- Anatomic Pathology, Tohoku University School of Medicine, Sendai, Miyagi, Japan.,Anatomical Pathology, Singapore General Hospital, Singapore, Singapore
| | - Aye Aye Thike
- Anatomical Pathology, Singapore General Hospital, Singapore, Singapore.,Duke-NUS Medical School, Singapore, Singapore
| | | | | | | | - Huihua Li
- Health Services Research Unit, Singapore General Hospital, Singapore, Singapore.,Centre for Quantitative Medicine, Duke-NUS Medical School, Singapore, Singapore
| | | | - Xiao-Yang Chen
- Anatomical Pathology, Singapore General Hospital, Singapore, Singapore.,Anatomy, National University Singapore Yong Loo Lin School of Medicine, Singapore, Singapore
| | - Joe Poh Sheng Yeong
- Anatomical Pathology, Singapore General Hospital, Singapore, Singapore.,Integrative Biology for Theranostics, Institute of Molecular and Cell Biology, Singapore, Singapore
| | - Hironobu Sasano
- Anatomic Pathology, Tohoku University School of Medicine, Sendai, Miyagi, Japan.,Pathology, Tohoku University Hospital, Sendai, Miyagi, Japan
| | - Puay Hoon Tan
- Duke-NUS Medical School, Singapore, Singapore .,Anatomy, National University Singapore Yong Loo Lin School of Medicine, Singapore, Singapore.,Pathology, Singapore General Hospital, Singapore, Singapore
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Giovannelli P, Di Donato M, Galasso G, Di Zazzo E, Medici N, Bilancio A, Migliaccio A, Castoria G. Breast cancer stem cells: The role of sex steroid receptors. World J Stem Cells 2019; 11:594-603. [PMID: 31616537 PMCID: PMC6789191 DOI: 10.4252/wjsc.v11.i9.594] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Revised: 05/06/2019] [Accepted: 08/21/2019] [Indexed: 02/06/2023] Open
Abstract
Breast cancer (BC) is the most common cancer among women, and current available therapies often have high success rates. Nevertheless, BC might acquire drug resistance and sometimes relapse. Current knowledge about the most aggressive forms of BC points to the role of specific cells with stem properties located within BC, the so-called “BC stem cells” (BCSCs). The role of BCSCs in cancer formation, growth, invasiveness, therapy resistance and tumor recurrence is becoming increasingly clear. The growth and metastatic properties of BCSCs are regulated by different pathways, which are only partially known. Sex steroid receptors (SSRs), which are involved in BC etiology and progression, promote BCSC proliferation, dedifferentiation and migration. However, in the literature, there is incomplete information about their roles. Particularly, there are contrasting conclusions about the expression and role of the classical BC hormonal biomarkers, such as estrogen receptor alpha (ERα), together with scant, albeit promising information concerning ER beta (ERβ) and androgen receptor (AR) properties that control different transduction pathways in BCSCs. In this review, we will discuss the role that SRs expressed in BCSCs play to BC progression and recurrence and how these findings have opened new therapeutic possibilities.
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Affiliation(s)
- Pia Giovannelli
- Department of Precision Medicine, University of Campania “L. Vanvitelli”, Naples 80138, Italy
| | - Marzia Di Donato
- Department of Precision Medicine, University of Campania “L. Vanvitelli”, Naples 80138, Italy
| | - Giovanni Galasso
- Department of Precision Medicine, University of Campania “L. Vanvitelli”, Naples 80138, Italy
| | - Erika Di Zazzo
- Department of Precision Medicine, University of Campania “L. Vanvitelli”, Naples 80138, Italy
| | - Nicola Medici
- Department of Precision Medicine, University of Campania “L. Vanvitelli”, Naples 80138, Italy
| | - Antonio Bilancio
- Department of Precision Medicine, University of Campania “L. Vanvitelli”, Naples 80138, Italy
| | - Antimo Migliaccio
- Department of Precision Medicine, University of Campania “L. Vanvitelli”, Naples 80138, Italy
| | - Gabriella Castoria
- Department of Precision Medicine, University of Campania “L. Vanvitelli”, Naples 80138, Italy
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Song P, Li Y, Dong Y, Liang Y, Qu H, Qi D, Lu Y, Jin X, Guo Y, Jia Y, Wang X, Xu W, Quan C. Estrogen receptor β inhibits breast cancer cells migration and invasion through CLDN6-mediated autophagy. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2019; 38:354. [PMID: 31412908 PMCID: PMC6694553 DOI: 10.1186/s13046-019-1359-9] [Citation(s) in RCA: 97] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/18/2019] [Accepted: 08/06/2019] [Indexed: 12/31/2022]
Abstract
Background Estrogen receptor β (ERβ) has been reported to play an anti-cancer role in breast cancer, but the regulatory mechanism by which ERβ exerts this effect is not clear. Claudin-6 (CLDN6), a tight junction protein, acts as a tumor suppressor gene in breast cancer. Our previous studies have found that 17β-estradiol (E2) induces CLDN6 expression and inhibits MCF-7 cell migration and invasion, but the underlying molecular mechanisms are still unclear. In this study, we aimed to investigate the role of ERβ in this process and the regulatory mechanisms involved. Methods Polymerase chain reaction (PCR) and western blot were used to characterize the effect of E2 on the expression of CLDN6 in breast cancer cells. Chromatin immunoprecipitation (ChIP) assays were carried out to confirm the interaction between ERβ and CLDN6. Dual luciferase reporter assays were used to detect the regulatory role of ERβ on the promoter activity of CLDN6. Wound healing and Transwell assays were used to examine the migration and invasion of breast cancer cells. Western blot, immunofluorescence and transmission electron microscopy (TEM) were performed to detect autophagy. Xenograft mouse models were used to explore the regulatory effect of the CLDN6-beclin1 axis on breast cancer metastasis. Immunohistochemistry (IHC) was used to detect ERβ/CLDN6/beclin1 expression in breast cancer patient samples. Results Here, E2 upregulated the expression of CLDN6, which was mediated by ERβ. ERβ regulated CLDN6 expression at the transcriptional level. ERβ inhibited the migration and invasion of breast cancer cells through CLDN6. Interestingly, this effect was associated with CLDN6-induced autophagy. CLDN6 positively regulated the expression of beclin1, which is a key regulator of autophagy. Beclin1 knockdown reversed CLDN6-induced autophagy and the inhibitory effect of CLDN6 on breast cancer metastasis. Moreover, ERβ and CLDN6 were positively correlated, and the expression of CLDN6 was positively correlated with beclin1 in breast cancer tissues. Conclusion Overall, this is the first study to demonstrate that the inhibitory effect of ERβ on the migration and invasion of breast cancer cells was mediated by CLDN6, which induced the beclin1-dependent autophagic cascade. Electronic supplementary material The online version of this article (10.1186/s13046-019-1359-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Peiye Song
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, 130021, Jilin, China
| | - Yanru Li
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, 130021, Jilin, China
| | - Yuan Dong
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, 130021, Jilin, China
| | - Yingying Liang
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, 130021, Jilin, China
| | - Huinan Qu
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, 130021, Jilin, China
| | - Da Qi
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, 130021, Jilin, China
| | - Yan Lu
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, 130021, Jilin, China
| | - Xiangshu Jin
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, 130021, Jilin, China
| | - Yantong Guo
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, 130021, Jilin, China
| | - Yiyang Jia
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, 130021, Jilin, China
| | - Xinqi Wang
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, 130021, Jilin, China
| | - Wenhong Xu
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, 130021, Jilin, China
| | - Chengshi Quan
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, 130021, Jilin, China.
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Mukhopadhyay UK, Oturkar CC, Adams C, Wickramasekera N, Bansal S, Medisetty R, Miller A, Swetzig WM, Silwal-Pandit L, Børresen-Dale AL, Creighton CJ, Park JH, Konduri SD, Mukhopadhyay A, Caradori A, Omilian A, Bshara W, Kaipparettu BA, Das GM. TP53 Status as a Determinant of Pro- vs Anti-Tumorigenic Effects of Estrogen Receptor-Beta in Breast Cancer. J Natl Cancer Inst 2019; 111:1202-1215. [PMID: 30990221 PMCID: PMC6855950 DOI: 10.1093/jnci/djz051] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Revised: 12/28/2018] [Accepted: 04/01/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Anti-tumorigenic vs pro-tumorigenic roles of estrogen receptor-beta (ESR2) in breast cancer remain unsettled. We investigated the potential of TP53 status to be a determinant of the bi-faceted role of ESR2 and associated therapeutic implications for triple negative breast cancer (TNBC). METHODS ESR2-TP53 interaction was analyzed with multiple assays including the in situ proximity ligation assay. Transcriptional effects on TP53-target genes and cell proliferation in response to knocking down or overexpressing ESR2 were determined. Patient survival according to ESR2 expression levels and TP53 mutation status was analyzed in the basal-like TNBC subgroup in the Molecular Taxonomy of Breast Cancer International Consortium (n = 308) and Roswell Park Comprehensive Cancer Center (n = 46) patient cohorts by univariate Cox regression and log-rank test. All statistical tests are two-sided. RESULTS ESR2 interaction with wild-type and mutant TP53 caused pro-proliferative and anti-proliferative effects, respectively. Depleting ESR2 in cells expressing wild-type TP53 resulted in increased expression of TP53-target genes CDKN1A (control group mean [SD] = 1 [0.13] vs ESR2 depletion group mean [SD] = 2.08 [0.24], P = .003) and BBC3 (control group mean [SD] = 1 [0.06] vs ESR2 depleted group mean [SD] = 1.92 [0.25], P = .003); however, expression of CDKN1A (control group mean [SD] = 1 [0.21] vs ESR2 depleted group mean [SD] = 0.56 [0.12], P = .02) and BBC3 (control group mean [SD] = 1 [0.03] vs ESR2 depleted group mean [SD] = 0.55 [0.09], P = .008) was decreased in cells expressing mutant TP53. Overexpressing ESR2 had opposite effects. Tamoxifen increased ESR2-mutant TP53 interaction, leading to reactivation of TP73 and apoptosis. High levels of ESR2 expression in mutant TP53-expressing basal-like tumors is associated with better prognosis (Molecular Taxonomy of Breast Cancer International Consortium cohort: log-rank P = .001; hazard ratio = 0.26, 95% confidence interval = 0.08 to 0.84, univariate Cox P = .02). CONCLUSIONS TP53 status is a determinant of the functional duality of ESR2. Our study suggests that ESR2-mutant TP53 combination prognosticates survival in TNBC revealing a novel strategy to stratify TNBC for therapeutic intervention potentially by repurposing tamoxifen.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Gokul M Das
- Correspondence to: Gokul M. Das, PhD, Department of Pharmacology and Therapeutics, Center for Genetics and Pharmacology, Roswell Park Comprehensive Cancer Center, Elm & Carlton Streets, Buffalo, NY 14263 (e-mail: )
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44
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Qiu YB, Liao LY, Jiang R, Xu M, Xu LW, Chen GG, Liu ZM. PES1 promotes the occurrence and development of papillary thyroid cancer by upregulating the ERα/ERβ protein ratio. Sci Rep 2019; 9:1032. [PMID: 30705367 PMCID: PMC6355968 DOI: 10.1038/s41598-018-37648-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Accepted: 12/07/2018] [Indexed: 02/07/2023] Open
Abstract
PES1, a BRCT domain-containing protein, has been shown to play a role in modulating the balance and ratio between ERα and ERβ protein, which is involved in the occurrence and development of breast and ovarian cancer. However, its role in connection with the balance and ratio between ERα and ERβ protein in papillary thyroid cancer (PTC) remains unclear. Here, we found that ERα and ERβ were co-expressed in human PTC tissues and cells. ERα promoted and ERβ inhibited the proliferation, invasion and migration of PTC cells. PES1 modulated the balance between ERα and ERβ by elevating the ERα protein level and simultaneously reducing the ERβ protein level, then upregulating the ERα/ERβ protein ratio and promoting the proliferation, invasion and migration of PTC cells. In PTC tissues, PES1 protein level was positively correlated with the ERα protein level and negatively correlated with the ERβ protein level. The PES1 and ERα protein levels were gradually increased and the ERβ protein level was decreased by degree in the occurrence and development of PTC. Increased PES1 and ERα protein levels and decreased ERβ protein level were correlated with the aggressive behaviors of PTC patients such as large tumor size, extrathyroidal extension (ETE), lymph node metastasis (LNM), high BRAFV600E expression and high TNM stage. It is suggested that PES1 promotes the occurrence and development of PTC by elevating the ERα protein level and reducing the ERβ protein level, and then upregulating the ERα/ERβ protein ratio.
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Affiliation(s)
- Yi-Bo Qiu
- Department of Biochemistry and Molecular Biology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, China
| | - Ling-Yao Liao
- Department of Biochemistry and Molecular Biology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, China
| | - Rong Jiang
- Department of Pathology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, China
| | - Man Xu
- Department of Pathology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, China
| | - Lin-Wan Xu
- Department of Biochemistry and Molecular Biology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, China
| | - George G Chen
- Department of Surgery, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong, China
| | - Zhi-Min Liu
- Department of Biochemistry and Molecular Biology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, China.
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45
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Gandhi N, Das GM. Metabolic Reprogramming in Breast Cancer and Its Therapeutic Implications. Cells 2019; 8:E89. [PMID: 30691108 PMCID: PMC6406734 DOI: 10.3390/cells8020089] [Citation(s) in RCA: 152] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Revised: 01/20/2019] [Accepted: 01/22/2019] [Indexed: 12/22/2022] Open
Abstract
Current standard-of-care (SOC) therapy for breast cancer includes targeted therapies such as endocrine therapy for estrogen receptor-alpha (ERα) positive; anti-HER2 monoclonal antibodies for human epidermal growth factor receptor-2 (HER2)-enriched; and general chemotherapy for triple negative breast cancer (TNBC) subtypes. These therapies frequently fail due to acquired or inherent resistance. Altered metabolism has been recognized as one of the major mechanisms underlying therapeutic resistance. There are several cues that dictate metabolic reprogramming that also account for the tumors' metabolic plasticity. For metabolic therapy to be efficacious there is a need to understand the metabolic underpinnings of the different subtypes of breast cancer as well as the role the SOC treatments play in targeting the metabolic phenotype. Understanding the mechanism will allow us to identify potential therapeutic vulnerabilities. There are some very interesting questions being tackled by researchers today as they pertain to altered metabolism in breast cancer. What are the metabolic differences between the different subtypes of breast cancer? Do cancer cells have a metabolic pathway preference based on the site and stage of metastasis? How do the cell-intrinsic and -extrinsic cues dictate the metabolic phenotype? How do the nucleus and mitochondria coordinately regulate metabolism? How does sensitivity or resistance to SOC affect metabolic reprogramming and vice-versa? This review addresses these issues along with the latest updates in the field of breast cancer metabolism.
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Affiliation(s)
- Nishant Gandhi
- Department of Pharmacology and Therapeutics, Center for Genetics & Pharmacology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.
| | - Gokul M Das
- Department of Pharmacology and Therapeutics, Center for Genetics & Pharmacology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.
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Sachdeva G, Desouza J, Gadkar S, Jagtap D. Size, site, and signaling: Three attributes of estrogen receptors. BIOMEDICAL RESEARCH JOURNAL 2019. [DOI: 10.4103/bmrj.bmrj_24_19] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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47
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Younes M, Ly CJ, Singh K, Ertan A, Younes PS, Bailey JM. Expression of estrogen receptor beta isoforms in pancreatic adenocarcinoma. Oncotarget 2018; 9:37715-37720. [PMID: 30701026 PMCID: PMC6340876 DOI: 10.18632/oncotarget.26503] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Accepted: 12/13/2018] [Indexed: 01/18/2023] Open
Abstract
Limited studies have shown that some patients with pancreatic adenocarcinoma (PAC) may benefit from treatment with tamoxifen. PAC has been shown to be largely negative for estrogen receptor alpha (ER-alpha). The aim of this pilot study was to investigate ER-beta expression in human PAC. Sections of tissue microarray with 18 evaluable cases of human PAC were stained by immunohistochemistry (IHC) for ER-beta1, ER-beta2, ER-beta5, and Cyclin A. The levels of ER-beta isoform expression and the S-phase fraction (SPF) were determined using quantitative digital image analysis. Higher mean and median ER-beta2 levels correlated with male sex (p = 0.057 and p = 0.035, respectively), older age (p = 0.005 and p = 0.006, respectively), and lower pT stage (p = 0.008 and p = 0.009). Mean and median ER-beta5 levels correlated negatively with SPF (p = 0.021 and p = 0.047, respectively). Mean ER-beta1 expression did not correlate with any of the above mentioned clinicopathologic factors. The findings in this pilot study, although should be considered preliminary, suggest that some ER-beta isoforms may play a role in the biology of PAC. Additional larger studies are needed to confirm our findings, and to determine whether ER-beta may be considered for future targeted therapy.
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Affiliation(s)
- Mamoun Younes
- Departments of Pathology and Laboratory Medicine, University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX, USA
| | - Charles J. Ly
- Departments of Pathology and Laboratory Medicine, University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX, USA
| | - Kanchan Singh
- Department of Medicine, Section of Gastroenterology, Hepatology and Nutrition, University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX, USA
| | - Atilla Ertan
- Department of Medicine, Section of Gastroenterology, Hepatology and Nutrition, University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX, USA
| | - Pamela S. Younes
- Departments of Pathology and Laboratory Medicine, University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX, USA
| | - Jennifer M. Bailey
- Department of Medicine, Section of Gastroenterology, Hepatology and Nutrition, University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX, USA
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Güler SA, Şimşek T, Pösteki G, Güreşin A, Çınar S, Onbaşılar U, Cantürk NZ. A Very Rare Reason for Gastric Perforation, Caused by Gastric Metastasis of Breast Cancer: Case Presentation. Eur J Breast Health 2018; 15:59-62. [PMID: 30816356 DOI: 10.5152/ejbh.2018.4285] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Accepted: 10/02/2018] [Indexed: 12/28/2022]
Abstract
Breast cancer is the mostly seen malignancy of women. Breast cancer causes lung, bone, liver and brain metastasis. On the other hand, gastric metastasis of breast cancer is a rarely seen metastasis. For this reason, it may be misdiagnosed or diagnosed after its morbid or mortal complications occurred. This may also result as a delay of breast cancers primary treatment. If occurred the best tool is immunohistochemical panels especially gross cystic disease fluid protein 15 (GCDFP-15) for exact diagnosis. In our case, a gastric metastasis of breast cancer is presented which was admitted with the acute abdominal findings caused by its result as gastric perforation and diagnosed by GCDFP-15 immunohistochemical panel.
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Affiliation(s)
- Sertaç Ata Güler
- Department of General Surgery, Kocaeli University School of Medicine, Kocaeli, Turkey
| | - Turgay Şimşek
- Department of General Surgery, Kocaeli University School of Medicine, Kocaeli, Turkey
| | - Gökhan Pösteki
- Department of General Surgery, Kocaeli University School of Medicine, Kocaeli, Turkey
| | - Alican Güreşin
- Department of General Surgery, Kocaeli University School of Medicine, Kocaeli, Turkey
| | - Saffet Çınar
- Department of General Surgery, Kocaeli University School of Medicine, Kocaeli, Turkey
| | - Umut Onbaşılar
- Department of General Surgery, Kocaeli University School of Medicine, Kocaeli, Turkey
| | - Nuh Zafer Cantürk
- Department of General Surgery, Kocaeli University School of Medicine, Kocaeli, Turkey
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Perkins MS, Louw-du Toit R, Africander D. Hormone Therapy and Breast Cancer: Emerging Steroid Receptor Mechanisms. J Mol Endocrinol 2018; 61:R133-R160. [PMID: 29899079 DOI: 10.1530/jme-18-0094] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Revised: 06/04/2018] [Accepted: 06/12/2018] [Indexed: 12/31/2022]
Abstract
Although hormone therapy is widely used by millions of women to relieve symptoms of menopause, it has been associated with several side-effects such as coronary heart disease, stroke and increased invasive breast cancer risk. These side-effects have caused many women to seek alternatives to conventional hormone therapy, including the controversial custom-compounded bioidentical hormone therapy suggested to not increase breast cancer risk. Historically estrogens and the estrogen receptor were considered the principal factors promoting breast cancer development and progression, however, a role for other members of the steroid receptor family in breast cancer pathogenesis is now evident, with emerging studies revealing an interplay between some steroid receptors. In this review, we discuss examples of hormone therapy used for the relief of menopausal symptoms, highlighting the distinction between conventional hormone therapy and custom-compounded bioidentical hormone therapy. Moreover, we highlight the fact that not all hormones have been evaluated for an association with increased breast cancer risk. We also summarize the current knowledge regarding the role of steroid receptors in mediating the carcinogenic effects of hormones used in menopausal hormone therapy, with special emphasis on the influence of the interplay or crosstalk between steroid receptors. Unraveling the intertwined nature of steroid hormone receptor signaling pathways in breast cancer biology is of utmost importance, considering that breast cancer is the most prevalent cancer among women worldwide. Moreover, understanding these mechanisms may reveal novel prevention or treatment options, and lead to the development of new hormone therapies that does not cause increased breast cancer risk.
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Affiliation(s)
- Meghan S Perkins
- Department of Biochemistry, Stellenbosch University, Matieland, South Africa
| | - Renate Louw-du Toit
- Department of Biochemistry, Stellenbosch University, Matieland, South Africa
| | - Donita Africander
- Department of Biochemistry, Stellenbosch University, Matieland, South Africa
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50
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Estrogen receptor-beta is a potential target for triple negative breast cancer treatment. Oncotarget 2018; 9:33912-33930. [PMID: 30338035 PMCID: PMC6188058 DOI: 10.18632/oncotarget.26089] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Accepted: 07/12/2018] [Indexed: 12/31/2022] Open
Abstract
Triple Negative breast cancer (TNBC) is a subtype of breast cancer that lacks the expression of estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2. TNBC accounts for 15-20% of all breast cancer cases but accounts for over 50% of mortality. We propose that Estrogen receptor-beta (ERβ) and IGF2 play a significant role in the pathogenesis of TNBCs, and could be important targets for future therapy. Tissue microarrays (TMAs) from over 250 TNBC patients' were analyzed for ERβ and IGF2 expression by immunohistochemistry. Expression was correlated with clinical outcomes. In addition, TNBC cell lines Caucasians (CA): MB-231/BT549 and African Americans (AAs): MB-468/HCC70/HCC1806 were used to investigate the effect of hormonal and growth factor regulation on cell proliferation. TMAs from AAs had higher expression of ERβ and IGF2 expression when compared to CA. ERβ and IGF2 were found to be upregulated in our TNBC cell lines when compared to other cell types. TNBC cells treated with ERβ agonist displayed significant increase in cell proliferation and migration when compared to controls. AA tissue samples from TNBC patients had higher expression of ERβ. African-American breast cancer TNBC tissue samples from TNBC patients have higher expression of ERβ. In addition, TNBC cell lines were also found to express high levels of ERβ. IGF2 increased transcription of ERβ in TNBC cells. Understanding the mechanisms of IGF2/ERβ axis in TNBC tumors could provide an opportunity to target this aggressive subtype of breast cancer.
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