The role of bile acids to ameliorate obesity driven triple negative breast cancer

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Triple negative breast cancer (TNBC) is an aggressive subtype, associated with obesity, that disproportionately affects young and minority women; with no molecularly targeted therapies for this subtype, outcomes remain very poor. Obesity induces immune and metabolic changes to the tumor microenvironment that lead to higher risk of invasion, metastases, and recurrence, as well as poor response to therapy and higher mortality. Despite known associations, the mechanistic interdependencies between obesity and breast cancer remain unclear. Patients who underwent bariatric surgery had significantly reduced risk of breast cancer, including TNBC. My premise is that underlying beneficial mechanisms uniquely associated with surgically induced weight loss can be capitalized upon to mimic the benefits of surgery to reduce cancer risk. Therefore, the ultimate goal of this proposal is to test novel pharmacologic treatments to improve TNBC outcomes informed by diet and surgical interventions. A potential mediator of benefits after surgical weight loss is highly elevated circulating bile acids. The bile acid receptor, farnesoid X receptor (FXR), mediated weight loss and metabolic benefits of bariatric surgery. We present striking preliminary data for a role of FXR activation in reducing TNBC progression in vivo with significant changes in immune cells suggesting improved anti-tumor immunity. We also demonstrate FXR activation blunts proliferation, migration and invasion in human and murine TNBC cells in vitro. In patients, we observed that FXR is a significant predictor of relapse-free survival in TNBC. Therefore, I hypothesize that activating FXR, via elevated bile acids secondary to bariatric surgery or pharmacologically targeting FXR, will improve TNBC outcomes. With my training and expertise of my mentoring team, I am well poised to rigorously investigate underlying bile acidFXRTNBC mechanisms to determine therapeutic efficacy of FXR agonism. Aim 1 will use a preclinical TNBC model to determine to what extent elevated bile acids abrogate obesity- associated TNBC progression using an innovative bile diversion bariatric surgery. Aim 2 will determine if pharmacologic FXR activation using an existing FDA-approved FXR agonist will improve therapeutic efficacy for TNBC. Using loss of function models Aim 2 will determine the contribution of FXR in tumor intrinsic vs. extrinsic anti-tumor immune-mediated mechanisms to reduce TNBC. Outcomes from this proposal will be high impact as the first to test the dependence of TNBC on bile acids and FXR. A limited understanding of the mechanistic links between breast cancer and obesity pose a fundamental obstacle to helping patients. Since obesity rates are rising, completion of this project will ultimately address an urgent unmet clinical need in TNBC treatment as well as provide an exceptional F32 training opportunity.