Role of the androgen receptor in the human breast epithelium

Breast cancer is the most common malignancy in women worldwide and understanding the risk factors affecting it is key for prevention. The relative risk of developing breast cancer is related to exposure to both endogenous hormones and exogenous natural and synthetic steroid hormone receptor agonists. Hormonal contraception exposes million of women to synthetic progesterone receptor (PR) agonists, so-called progestins, and transiently increases breast cancer risk. However, how contraceptive progestins affect the human breast epithelium is poorly understood, partially because of the lack of adequate preclinical models. We hypothesized that progestins are not all equal with regards to their effects on the human breast epithelium. To test this hypothesis, we employed reduction mammoplasty specimens derived from 40 women to establish in vivo preclinical models and show that different progestins have distinct biological activities in the breast epithelium depending on their androgenic properties. Androgen receptor inhibition interfered cell proliferation driven by the androgenic levonorgestrel, suggesting that androgenic progestins rely on AR to drive cell growth. Hence, we aimed to characterize the role that AR signaling pathway plays in the human breast epithelium, and we hypothesized that AR activation is sufficient for HBECs proliferation. We show that DHT treatments promote the proliferation of human cells dependently on its plasma concentrations, while having opposite effects in the murine mammary epithelium. Image analysis suggests that DHT-driven proliferation occurs in a paracrine fashion. Global gene expression analyses of hormone-treated PDXs revealed that AR signaling activation strongly perturbs the transcriptional profile of HBECs and identified mTORc1 signaling as a targetable mediator of AR-driven proliferation. Interestingly, transcriptional profiling of progestin-treated PDXs detected mTORc1 signaling to be specifically enriched upon androgenic progestin treatments in HBECs, suggesting the AR-mTORc1 axis as a hitherto uncharacterized growth-promoting mechanism in HBECs. We conclude that AR signaling has a hitherto uncharacterized proliferative role in the breast epithelium which warrants caution when prescribing androgenic treatments, with important implications for breast cancer prevention.