Abstract 5568: CYP17A1 and abiraterone: Implications for breast cancer endocrine therapy

Abstract

Abstract The cytochrome P450 17A1 (CYP17A1) inhibitor abiraterone, which blocks synthesis of all steroid hormones including androgens and estrogens, is an effective treatment for castrate resistant prostate cancer. Its utility for treating hormone receptor-positive breast cancer has yet to be established. In prostate cancer, the anti-proliferative effects of abiraterone are mediated by inhibiting CYP17A1 activity resulting in a significant reduction in circulating concentrations of the sex steroids dehydroepiandrosterone (DHEA), androstenedione, testosterone, and dihydrotestosterone (DHT). Recently, it has been proposed that the reduction in aromatizable androgens by abiraterone may make this drug useful for the management of hormone-dependent breast cancer. However, data from our lab suggests that abiraterone has estrogenic properties and can induce proliferation in breast cancer cells expressing the estrogen receptor (ER). Crystal violet assays were used to assess abiraterone-induced proliferation in the ER-positive, estrogen-dependent breast cancer cell lines MCF-7 and T47D. We show that abiraterone induced a dose dependent increase in cell proliferation with an IC50 of 3.7 μM and maximal stimulation (200%) observed at 8μM, compared to vehicle treated cells. Abiraterone also induced the expression of the ER response gene, GREB1. Abiraterone-induced proliferation and gene expression was blocked by increasing doses of the selective estrogen receptor down-regulator (SERD) fulvestrant. Abiraterone induced the dose-dependent expression of luciferase in MCF-7 cells transfected with an estrogen responsive luciferase reporter construct. In conclusion, our data suggest that abiraterone can induce ER-positive breast cancer cell proliferation in vitro by acting as a weak ER agonist. Further studies are underway to determine whether estrogenic effects of abiraterone are also observed using in vivo models of ER response. If abiraterone exhibits estrogenic effects in vivo then these data would suggest that abiraterone should be combined with an ER antagonist if used for the clinical management of women with ER+ tumors. Citation Format: Cameron P. Capper, Michael D. Johnson, José M. Larios, James M. Rae. CYP17A1 and abiraterone: Implications for breast cancer endocrine therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5568. doi:10.1158/1538-7445.AM2014-5568