Wednesday, April 2, 2025
4/2/2025
The pro-metastatic role of androgen receptor in estrogen receptor mutated breast cancer - The five-year survival rate for metastatic breast cancer (MBC) remains less than 50% and nearly all patients eventually succumb to the disease; therefore, understanding pro-metastatic mechanisms for adjuvant therapy resistant breast cancer (BC) remains a critical unmet need in the field. Our long-term goal is to elucidate adaptive changes that enable BC cells to persist and recur as metastatic disease and to reveal new therapeutic vulnerabilities. The standard of care adjuvant therapy for estrogen receptor alpha positive (ER+) BC in postmenopausal women (the most common form of the disease) is estrogen (E2)-deprivation achieved through aromatase inhibitors (AI). AI therapy blocks conversion of androgens to E2, effectively decreasing E2 production, but increases circulating and intra-tumoral androgens. The Richer laboratory has published extensively on mechanisms by which androgen receptors (AR) interact with driving pathways in the three main BC subtypes. Recently, the Yu laboratory independently discovered that AR supports tumor cell survival under cellular stress incurred by E2-deprivation (simulating AI therapy) and reactive oxygen species (ROS) incurred by anchorage independence and may thereby facilitate relapse as metastatic disease. Indeed, the two labs independently discovered that AR is further elevated in BC cells with ER hot spot mutations that are exclusively detectable in MBCs following resistance to AI therapy. Since surviving E2-deprivation therapy and anchorage independence is critical to metastatic progression of ER+ BC, understanding the role of AR in these conditions is highly relevant for MBC. It is known that a critical barrier for circulating tumor cell (CTC) survival during metastasis is to overcome the high level of ROS in anchorage independent conditions. These data led to our hypothesis that AR promotes reduction of ROS and CTC survival thereby promotes metastasis. We combine expertise of AR signaling (Richer) and metastasis (Yu) and use mutant ER BC cell lines, patient derived CTC lines, patient derived xenografts (PDX), and murine syngeneic models to test the following aims. We will evaluate the role and mechanisms of AR upregulation during estrogen deprivation and anchorage-independent survival of ER mutant BC cells, by examining the ROS levels impacted by AR activity, AR binding profile and downstream targets in vitro, as well as the mechanism for AR upregulation in anchorage independent condition (Aim 1). We will examine the contribution and mechanisms of AR mediated pro-metastatic signals in vivo, via evaluating the impact of AR inhibition on metastatic potential in mutant ER cells, the AR levels in CTCs and metastasis, as well as the binding profiles of AR and the role of its downstream targets in promoting metastases (Aim 2). This application is aimed to determine how AR supports ER mutant BC to resist stresses incurred during metastatic progression, with the goal of devising better therapeutic strategies to reduce mortality from MBC.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).