The Role of Estrogen Receptor Alpha in Durotactic Migration and Invasion in Breast Cancer

Abstract

Breast cancer (BrCa) is the second most deadly cancer for women. About 1 in 8 women will develop breast cancer over her lifetime, with 80% of those cases being estrogen receptor positive (ER+). Although ER+ breast tumors are associated with less aggressive clinicopathological features, more women die from ER+ BrCa than any other subtype. This is largely due to the high incidence of ER+ BrCa with a greater than 20% metastasis rate. Understanding the role of estrogen receptor alpha (ERα) in driving tumor progression and ultimately metastasis is key to developing potential therapeutic options for patients. For tumors to progress, cancer cells must migrate and invade into the surrounding tumor microenvironment (TME), which consists of a complex system of both biochemical and biophysical components. Durotaxis, which is the directional migration towards increasing matrix stiffness, has been shown to have biological implications ranging from development processes and wound healing to cancer. However, the mechanism regulating the response of ER+ BrCa to the surrounding matrix is not well understood. We show that ERα promotes mechanosensing and durotaxis in breast cancer cells in a stiff environment through the formation of the Ena/VASP protein, EVL, mediated protrusions. We also demonstrate the dichotomous role of ERα in suppressing invasion through the generation of suppressive cortical actin bundles (SCABs) in a soft environment. While future studies are needed to fully characterize the mechanism and interacting proteins which form SCABs and protrusions, our work demonstrates the importance of the mechanical properties of the TME.