Estrogen receptor signaling in the human breast epithelium

Breast cancer is the most diagnosed malignancy in women worldwide, making effective prevention strategies crucial. Hormonal contraceptives, consisting of a synthetic progesterone receptor agonist alone or in combination with an estrogen, are used by millions of women worldwide and have been linked to increased breast cancer risk. To date, their mechanisms of action on human breast epithelial cells (HBECs) remain elusive. We have previously shown that the mouse intraductal model in which HBECs are grafted to the milk ducts of immunocompromised mice preserves hormone receptor expression. We exploited this model to assess if 17alpha-ethinyl estradiol (EE2), the predominant estrogenic component of combined oral contraceptives (OCs), has a distinct activity profile from that of the natural estrogen 17beta-estradiol (E2) in HBECs and characterized methods for stable and long-term estrogen delivery. We show that both E2 and EE2 increased the in vivo growth of HBECS, with the former estrogen being slightly more potent. E2 and EE2-treated glands showed similar proliferation indices 21 days after treatment and displayed similar transcriptomic profiles with robust gene signatures. Our data suggest that the increased risk of breast cancer associated with the use of OCs is not attributed to EE2, but rather to the progestin used in combination. We recently showed that progestins with androgenic properties promote HBEC proliferation but progestins with anti-androgenic properties do not.