Regulation of Cancer Cell Invasion by the Estrogen Receptor in ER+ Breast Cancer

Abstract

Estrogen receptor-positive (ER+) breast tumors account for 75% of diagnosed breast cancer in the United States. These breast tumors are defined by their dependency on the hormone estrogen for continued growth. Adjuvant endocrine therapy is frequently used to treat patients afflicted with ER+ breast cancer, during which ER inhibitors are used to suppress tumor growth. However, several epidemiological studies examining ER+ breast cancer in patients treated with estrogen show a significant decrease in cancer cell invasion, suggesting ER signaling may play a role in regulating invasion. While the mitogenic effects of estrogen on ER+ breast cancer are well studied, the mechanisms of regulating cancer cell invasion by ER signaling have not been characterized. In this dissertation, we show that estrogen-ER signaling suppresses cancer cell dissemination through the generation of Suppressive Cortical Actin Bundles (SCABs) at the leading edge of the cell. The formation of these actin structures are facilitated by the expression of the Ena/VASP protein family member EVL, which is transcriptionally regulated by ERs, and suppresses cancer cell invasion both in vitro and in vivo. Additionally, we find that suppressing ER activity by using clinical ER inhibitors used during adjuvant endocrine therapy suppresses EVL expression and promotes invasion. From these results, we propose a model in which ER activity regulates invasion by suppressing cancer cell dissemination through EVL-mediated actin remodeling, highlighting ER as a regulator of both tumor growth and tumor invasion in ER+ breast cancer.