Estrogen therapies enhance mammary carcinogenesis in aging gerbil females under endocrine disruption.

Abstract

Breast cancer is closely associated with the hormonal sensitization that the mammary gland (MG) undergoes. We evaluated the effects of endogenous (E2) and synthetic (EE2) estrogens, commonly used as hormonal therapies during menopause, in a context of a pro-carcinogenic environment of endocrine disruption. This scenario was modeled to mimic the menopausal involution of the MG during aging in the Mongolian gerbil experimental model under previous bisphenol A exposure, during pregnancy and lactation. Our findings revealed significant remodeling of the epithelial compartment, characterized by increased branching density and loss of normal features, including decreased CD117+ luminal cells and loss of E-cadherin expression. Hormonal therapy with E2 or EE2 led to the development of epithelial lesions, characterized by an increase in invasive microcarcinomas and a decrease in basal (p63+α-SMA-) and myoepithelial (p63+α-SMA+) progenitor cells, contributing to increased neoplastic invasiveness. These changes were orchestrated by overexpression of EZH2 and a decrease in BRCA1, indicating a poor prognosis, especially for EE2. Furthermore, an imbalance between proliferation (PH-H3cells) and apoptosis (cleaved caspase 3) was observed in the MG of females treated with E2 and EE2. Additionally, distinct hormone receptor profiles were identified, with consistent upregulation of ERα and concomitant downregulation of ERβ and PR, particularly in EE2-treated MG. These alterations may contribute to the observed dysregulation of proliferation and apoptosis. Our results demonstrate that estrogenic hormonal therapies promote neoplastic progression of the aging MG previously subjected to endocrine disruption.