Vitamin D and androgen receptor-targeted therapy for triple-negative breast cancer.
Anti-estrogen and anti-HER2 treatments have been among the first and most successful examples of targeted therapy for breast cancer (BC). However, the treatment of triple-negative BC (TNBC) that lack estrogen receptor expression or HER2 amplification remains a major challenge. We previously discovered that approximately two-thirds of TNBCs express vitamin D receptor (VDR) and/or androgen receptor (AR) and hypothesized that TNBCs co-expressing AR and VDR (HR2-av TNBC) could be treated by targeting both of these hormone receptors. To evaluate the feasibility of VDR/AR-targeted therapy in TNBC, we characterized 15 different BC lines and identified 2 HR2-av TNBC lines and examined the changes in their phenotype, viability, and proliferation after VDR and AR-targeted treatment. Treatment of BC cell lines with VDR or AR agonists inhibited cell viability in a receptor-dependent manner, and their combination appeared to inhibit cell viability additively. Moreover, cell viability was further decreased when AR/VDR agonist hormones were combined with chemotherapeutic drugs. The mechanisms of inhibition by AR/VDR agonist hormones included cell cycle arrest and apoptosis in TNBC cell lines. In addition, AR/VDR agonist hormones induced differentiation and inhibited cancer stem cells (CSCs) measured by reduction in tumorsphere formation efficiency, high aldehyde dehydrogenase activity, and CSC markers. Surprisingly, we found that AR antagonists inhibited proliferation of most BC cell lines in an AR-independent manner, raising questions regarding their mechanism of action. In summary, AR/VDR-targeted agonist hormone therapy can inhibit HR2-av TNBC through multiple mechanisms in a receptor-dependent manner and can be combined with chemotherapy.
Sylvester Comprehensive Cancer Center, Department of Pathology, Braman Family Breast Cancer Institute and Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL, USA.|Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami, Miami, FL, USA.
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Thakkar
Sylvester Comprehensive Cancer Center, Department of Pathology, Braman Family Breast Cancer Institute and Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL, USA.
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Wang
Sylvester Comprehensive Cancer Center, Department of Pathology, Braman Family Breast Cancer Institute and Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL, USA.
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Picon-Ruiz
Department of Molecular and Cellular Pharmacology, University of Miami, Miami, FL, USA.
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Buchwald
Sylvester Comprehensive Cancer Center, Department of Pathology, Braman Family Breast Cancer Institute and Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL, USA. Tince@miami.edu.|, Biomedical Research Building, Room 926, 1501 NW 10th Avenue, Miami, FL, 33136, USA. Tince@miami.edu.
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D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D002117:Calcitriol / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D013196:Dihydrotestosterone / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D058990:Molecular Targeted Therapy; D011944:Receptors, Androgen / Q000378:metabolism*; D018167:Receptors, Calcitriol / Q000378:metabolism*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*
C410798:AR protein, human; D011944:Receptors, Androgen; D018167:Receptors, Calcitriol; C579457:VDR protein, human; D013196:Dihydrotestosterone; D002117:Calcitriol
Androgen receptor; Cancer stem cells; Hormone receptor; Triple-negative breast cancer; Vitamin D receptor