Hormone receptor expression in aging mammary tissue and carcinoma from a rodent model after xenoestrogen disruption

Abstract

Aims: Hormone receptors are the main markers applied for prognosis of breast cancer subtypes. Among modulators, exogenous chemical agents known as endocrine disruptors interact with certain receptors, triggering molecular pathways or increasing their expression. Bisphenol A (BPA), a xenoestrogen, interacts with several hormone receptors. Thus, our aim was to characterize the hormone receptor status in the mammary gland (MG) of aged female Mongolian gerbils exposed to BPA in pregnancy and lactation. Methods: We evaluated the expression of receptors for estrogens (ERα and ERβ), progesterone (PR), prolactin (PRL-R), HER2/ErbB2, and androgen (AR) in normal and hyperplastic mammary tissue and in carcinomas developed after BPA exposure. Key findings: BPA-exposed MG presented increased ERα, whereas ERβ, PR, and PRL-R showed lower expression. AR and HER2/ErbB2 showed similar expression in normal and hyperplastic tissue from control, vehicle, and BPA groups. Both receptors were found in cytoplasm and nucleus in BPA-induced carcinoma. We demonstrate the presence of EZH2 expression, an epigenetic and epithelial-mesenchymal transition (EMT) marker, with a high H-score in BPA-exposed MG, which was associated with poor prognosis of cancer. Co-localization of ERα and EZH2 was present in normal and carcinoma features, corroborating the installation of ERα-positive mammary cancer associated with the EMT process. Enhanced EZH2 in BPA-exposed mammary tissue could decrease ERβ expression and promote tumorigenesis progress through HER2/ErbB2. Significance: The present study proposes the Mongolian gerbil as an experimental model for mammary carcinogenesis studies, based on BPA disruption that triggers a phenotype of increased ERα/HER2 positivity and depletion of ERβ/PR expression.