Bisphenol A-induced mammary carcinogenesis in senile females: influence of hormone therapies on neoplastic development

Abstract

Breast Cancer is one of the most complex pathological conditions in women. In this context, Endocrine Disruptors (EDs) are substances with high carcinogenic potential. Bisphenol A (BPA), found in plastics and resins, is among the most widespread EDs in the environment. Studies have shown its ability to act as a tumor promoter in the Mammary Gland (MG). Moreover, co-exposure with other exogenous and endogenous agents may contribute to the development of severe neoplasms. In this sense, Hormone Therapies (HT), used in contraceptive methods and hormone replacement, present themselves as potential breast cancer promoters or suppressors. Thus, the present work aims to evaluate the effects of different estrogen and progestin compounds used in HT on the MG of aged gerbil females after carcinogenic induction by BPA. For this purpose, females will be exposed to BPA during gestation and lactation, two remodeling/susceptibility windows, and exposed from 12 months of age to 17-² Estradiol (E2); E2 + Progesterone (P4); Ethinyl Estradiol (EE2); EE2 + Cyproterone Acetate (CPA); or the phytoestrogen genistein, for 6 months (until 18 months of age). Histopathological analyses will be performed to evaluate tumor development and MG status, Immunohistochemistry (IHC), as well as Western Blotting of the PTEN/PI3K, AKT/mTOR, and YAP (Hippo pathway) molecular signaling pathways. Also, markers of proliferation (PHH3, MAPK, and NF-ºB) and apoptosis (caspase-3) will be quantified. Hormone receptors used for Breast Cancer prognosis (ER±, ER², PR, HER2, AR, PRL-R) and their co-expression with epigenetic markers (EZH2 and BRCA) will be evaluated. Finally, IHC and immunofluorescence will be performed to identify inflammatory repercussions (cytokines and inflammatory cells) induced by different hormone therapies. (AU)