Mammary gland development and EDC-driven cancer susceptibility in mesenchymal ER-knockout mice

Development of the mammary gland requires both proper hormone signaling and cross talk between the stroma and epithelium. While estrogen receptor (ER alpha) expression in the epithelium is essential for normal gland development, the role of this receptor in the stroma is less clear. Moreover, several lines of evidence suggest that mouse phenotypes of in utero exposure to endocrine disruption act through mesenchymal ER alpha in the developing fetus. We utilized a Twist2-cre mouse line to knock out mesenchymal ER alpha. Herein, we assessed mammary gland development in the context of mesenchymal ER alpha deletion. We also tested the effect of in utero bisphenol A (BPA) exposure to alter the tumor susceptibility in the mouse mammary tumor virus-neu (MMTV-neu) breast cancer mouse model. Mesenchymal ER alpha deletion resulted in altered reproductive tract development and atypical cytology associated with estrous cycling. The mammary gland demonstrated mature epithelial extension unlike complete ER alpha-knockout mice, but ductal extension was delayed and reduced compared to ER alpha-competent mice. Using the MMTV-Neu cancer susceptibility model, ER alpha-intact mice exposed to BPA had reduced tumor-free survival and overall survival compared to BPA-exposed mice having mesenchymal ER alpha deletion. This difference is specific for BPA exposure as vehicle-treated animals had no difference in tumor development between mice expressing and not expressing mesenchymal ER alpha. These data demonstrate that mesenchymal ER alpha expression is not required for ductal extension, nor does it influence cancer risk in this mouse model but does influence the cancer incidence associated with in utero BPA exposure.