title: The CYP17A1 inhibitor abiraterone exhibits estrogen receptor agonist activity in breast cancer.
abstract: Cytochrome P450 17A1 (CYP17A1) is the requisite enzyme for synthesis of sex steroids, including estrogens and androgens. As such, inhibition of CYP17A1 is a target for inhibiting the growth of hormone-dependent cancers including prostate and breast cancer. Abiraterone, is a first in class potent and selective CYP17A1 inhibitor that has been approved for the treatment of castration-resistant prostate cancer. Given that, androgens are the precursors for estrogen production, it has been proposed that abiraterone could be an effective form of treatment for estrogen receptor (ER)-positive breast cancer, though its utility in this context has yet to be established. Abiraterone has a core steroid-like chemical structure, and so we hypothesized that it may bind to nuclear steroid receptors including ER and have estrogenic activity. We tested this hypothesis by investigating abiraterone's ability to directly modulate ER signaling in breast cancer cell line models. We show that abiraterone directly activates ER, induces ER-target gene expression, and elicits estrogen-response-element reporter activity in the ER-positive cell lines MCF-7 and T47D. Abiraterone also induced cell proliferation by ~2.5-fold over vehicle in both MCF-7 and T47D cells. Importantly, abiraterone-induced cell proliferation and ER-activity was blocked by the selective estrogen receptor downregulator (SERD) fulvestrant, confirming that abiraterone directly acts at the ER. These data suggest that abiraterone should be combined with other ER antagonists when used for the clinical management of ER-positive breast cancer.
authors.affiliation: Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
authors.forename: Cameron P
authors.initials: CP
authors.lastname: Capper
authors.affiliation: Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
authors.forename: José M
authors.initials: JM
authors.lastname: Larios
authors.affiliation: Department of Pharmacology and Chemical Biology, Women's Cancer Research Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Sikora
authors.affiliation: Department of Oncology, Georgetown University School of Medicine, Washington, DC, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Johnson
authors.affiliation: Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA. jimmyrae@med.umich.edu.|Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, 48109, USA. jimmyrae@med.umich.edu.
authors.forename: James M
authors.initials: JM
authors.lastname: Rae
mesh_terms: D000736:Androstenes / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D000077267:Fulvestrant; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D009363:Neoplasm Proteins / Q000235:genetics; D011960:Receptors, Estrogen / Q000378:metabolism*
chemical_list: D000736:Androstenes; C416830:GREB1 protein, human; D009363:Neoplasm Proteins; D011960:Receptors, Estrogen; D000077267:Fulvestrant; D004958:Estradiol; C089740:abiraterone
keywords: Abiraterone; CYP17A1; Estrogen receptor