ABSTRACT The racial disparity in breast cancer survival rates has largely been attributed to late-stage diagnoses and increased incidence of triple negative breast cancer in African American (AA) compared to non-Hispanic White (white) women. However, the latest statistics indicate that more than 50% of tumors in AA women are estrogen receptor positive (ER+). ER+ tumors are considered less aggressive and are typically treated effectively with endocrine therapies that target ER activity (i.e. tamoxifen) or estrogen production (i.e. aromatase inhibitors). Despite a generally favorable prognosis for women with ER+ breast cancer, AA women still have a greater risk than white women of dying from ER+ disease. We have found that AA women in the Chicago area have a 4 to 5-fold greater risk of death from ER+ breast cancer than white women, even after controlling for stage at diagnosis, treatment, and other known prognostic factors. This finding implies that biologic mechanisms are activated in ER+ breast cancer from AA women, resulting in resistance to endocrine therapy and a greater risk of relapse and death. Our overarching goal is to identify biological and molecular mechanisms contributing to the racial survival disparity in ER+ breast cancer patients. The goal of this proposal is to investigate the role of SQLE (squalene epoxidase), a key enzyme in the biosynthesis of sterols, cholesterol, and oxysterols, as a potential driver of poor outcome in AA women with ER+ tumors. We hypothesize that elevated SQLE in ER+ tumors of AA women leads to an accumulation of biologically active sterols that function to promote tumor cell proliferation and survival. Mechanistically, we expect these sterols to function by altering ER activity and reducing responsiveness to endocrine therapies. To investigate this, we propose 3 aims: 1) to define the mechanism by which SQLE is up-regulated in ER+ breast tumors in AA women; 2) to identify SQLE-regulated sterols that are associated with race in ER+ breast tumors, and 3) to assess the cellular function and therapeutic potential of SQLE in ER+ tumors of AA women. To accomplish these aims, we will utilize newly generated tumor collections and novel preclinical models from AA women, as well as an innovative method we developed to detect and analyze multiple sterol species. Overall, we expect to establish SQLE as a critical player in the racial disparity observed in survival of patients with ER+ breast cancer. Importantly, we expect to uncover two new mechanisms that may explain i) how SQLE contributes to early relapse and ii) why SQLE expression is elevated in ER+ tumors of AA women. Ultimately, this work has the potential to increase health equity by improving survival for AA women with ER+ breast cancer through the development of novel preventive and treatment strategies that target underlying molecular mechanisms contributing to disparate outcomes.