Abstract 1805: CYP3A4 regulation of androgen receptor signaling in ER+ breast cancer

Abstract

Abstract Purpose: Eighty percent of breast cancers that are estrogen receptor-positive (ER+) express AR. According to American Cancer Society, every two out of three women are ER+ and initially respond to estrogen-receptor targeted therapies but later almost 50% of breast cancers, despite the presence of ER, fail to respond. Acquired resistance to these therapies is common and portends a poor prognosis, frequently requiring the use of cytotoxic therapies. Our preliminary results indicate that endocrine-resistant tumors express higher levels of AR and may depend on AR for their growth. Hence AR targeted therapies may be appropriate for these resistant tumors. As we have recently demonstrated that CYP3A regulates androgen receptor signaling, we wish to ascertain the role of CYP3A in regulating AR in endocrine-resistant breast cancer. Methods: The ER+ cell lines MCF7 and T47D were used to study the role of AR in breast cancer. To study endocrine resistance in breast cancer, tamoxifen resistant MCF7 and T47D lines were generated with recurrent treatment of IC90 dosage of tamoxifen over 6 months’ time period. Cell fractionation, western blotting and q-RTPCR techniques were used to study the role of AR. siRNA inhibition of CYP3A4, the isoform expressed in breast, was used to study its role in regulating AR in breast cancer. Results: Our results indicate that both MCF7 and T47D express active AR, inducible by DHT and R1881. Similar to prostate cancer we also observe that AR in these lines is regulated by CYP3A4. Cell fractionation studies indicate that inhibition of CYP3A4 by siRNA results in reduced AR migration to the nucleus inhibiting its role as a transcription factor. Our results also indicate that tamoxifen resistant cell lines express increased levels of AR. Tamoxifen resistant cell lines respond to bicalutamide/enzalutamide with a lower IC50 value than the native cell lines, reflecting their AR dependence. The resistant cell lines also show increased AR nuclear migration with R1881 induction as compared to native breast cell lines. Conclusions: Endocrine-resistant breast cancer is sensitive to antiandrogen therapy. CYP3A4 may play an important role in endocrine-resistant breast cancer by negatively regulating AR activity. Citation Format: Priyatham Gorjala, Oscar Goodman Jr, Ranjana Mitra. CYP3A4 regulation of androgen receptor signaling in ER+ breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1805.