Targeting Estrogen Receptor-Beta in Triple-Negative Breast Cancer

摘要

Estrogen signaling is primarily mediated by two estrogen receptors (ERs), ER and ER . Triple negative breast cancer (TNBCs) is an aggressive breast cancer sutype that lacks expression of several therapeutic targets. Based on in vitro and clinical data, it is hypothesized that estrogen receptor (ER) could be targeted with selective ligands to inhibit the growth of TNBCs. The goal of the work completed over the course of this training program aimed to better understand the role of ER in TNBC and develop tools to target and detect ER in TNBCs. First, reporter cell lines with inducible ER or ER expression and an estrogen responsive luciferase reporter were developed to identify and characterize subtype selective estrogenic ligands. Second, a tumorigenic TNBC cell line was engineered with inducible ER expression to determine the effects of ER on the growth of TNBC cells in vitro and in vivo. These cells were also used to globally identify the ligand dependent and independent ER target genes using RNA sequencing. Finally, ER immunohistochemistry was optimized using xenografts and applied to a cohort of TNBCs to assess associations with clinicopathologic features. Not only does this work provide a foundation for further research into the role of ER in TNBC, it resulted in several publications, presentations, and a rich training experience for a future career in breast cancer research.