Examining the Estrogen Receptor as a Targetable Vulnerability at All Stages of ER+ Breast Cancer

Breast cancer is the most commonly diagnosed cancer in women, second in lethality to lung cancer. Approximately 70% of breast cancer tumors express estrogen receptor (ER), and therefore are considered ER positive (ER+). These cases are treated with endocrine therapy, targeted therapy specific to ER through inhibition of estrogen synthesis or direct interaction with ER, halting proliferative signaling. While effective at reducing breast cancer tumors and preventing progression, up to 50% of patients develop resistance to this treatment. A majority of returning tumors maintain ER expression, thereby responding to other classes of endocrine therapy. This thesis focuses on the development of novel endocrine therapies and their efficacy in a variety of endocrine therapy-resistant breast cancer cell models alone or in combination. The novel therapies include orally bioavailable selective ER degraders (SERDs) and selective human ER partial agonists (ShERPAs), both effective in resistance to selective ER modulator (SERM)-resistant breast cancer cell lines. ShERPAs also reduce viability of a SERD-resistant cell line. In addition to novel therapies, resistance within the breast cancer cell models was characterized, probing for vulnerabilities to be targeted with combination therapy. Enriched survival and proliferative pathways were investigated in an ER+ cell line resistant to all clinical endocrine therapies but sensitive to ShERPAs. Combination therapy to target these pathways was then explored with the ShERPA for improved antiproliferative activity. Combinations with the orally bioavailable SERD were also investigated for antiproliferative activity in the SERM-resistant cell lines. This thesis demonstrates the vulnerabilities of ER within endocrine therapy-resistant breast cancer and optimization of targeting these vulnerabilities.