Abstract 1807: Inter-individual variation in response to estrogen in the mammary gland

Abstract

Abstract Background: Previous research has highlighted the paradoxical nature of estrogen in both contributing to and reducing the risk of breast cancer. Exposure to xenoestrogens may affect this delicate balance between the protective effects of estrogen and its contribution to breast cancer risk. The effects of xenoestrogens may differ among individual women, as genetic diversity has been shown to impact responses to chemicals and breast cancer susceptibility. We hypothesize that there are subsets of individuals uniquely sensitive to estrogen and xenoestrogens. Methods: In order to identify high and low estrogen response groups, we utilized primary human breast tissues and primary human breast epithelial cells. Explant cultures of primary human breast tissues maintain the normal tissue architecture, while primary human breast epithelial cells are more efficiently used for mechanistic studies. Primary breast tissues were treated with 17β-estradiol (E2), an estrogen receptor alpha (ERα) specific agonist PPT, and an estrogen receptor beta (ERβ) specific agonist ERB041 in order to examine estrogen responsiveness. TUNEL assays were used to examine apoptotic responses. Because expression of estrogen receptor in primary human breast epithelial cells is lost in culture, we treat with TGFβ receptor inhibitors RepSox and SB431542 to restore estrogen receptor expression. We also take conditionally immortalized human breast epithelial cell (ciHMEC) lines and TERT immortalized normal breast epithelial cell lines and transfect in ESR1 to examine responses to E2 and xenoestrogens BP3 and PP. Results: Our results show that, based on quantitative PCR analysis of estrogen receptor target genes, individuals vary in response to estrogen receptor agonist treatment. Our results from treatment of primary breast epithelial cells with TGFβ inhibitors show an increase in the levels of ESR1 expression by 2-3 fold compared to control. We are testing whether this is sufficient to restore estrogen-induced responses. Current results from the ciHMEC and normal TERT immortalized breast epithelial cell lines also illustrate the differences in response among individuals. Some individuals have estrogenic responses at physiological doses of BP3 and PP which are similar to responses seen from treating with pregnancy levels of E2. Conclusions: These models demonstrate the variation in estrogenic responses between individual patient samples. Estrogenic compounds PPT, ERB041, PP, and BP3 can induce similar responses to those of E2 in certain individuals, as reflected in target gene expression and transactivation data. Responses to E2 and xenoestrogens vary among TERT immortalized lines and ciHMEC lines, just as responses to E2 and other estrogen receptor agonists varied among individual explant patient samples. The ciHMEC lines can be used to define the mechanistic differences in estrogen sensitivity among women. Citation Format: Karen A. Dunphy, Amye L. Black, Sallie S. Schneider, D Joseph Jerry. Inter-individual variation in response to estrogen in the mammary gland [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1807.