Metabolic adaptation in residual triple negative breast cancer following chemotherapy

PROJECT SUMMARY TNBC is a subtype of breast cancer predominated by major health disparity. African American (AA) women have a disproportionately higher incidence of TNBC than do European American (EA) women. In fact, AA women are twice as likely to be diagnosed with TNBC as are women of other races. Within TNBC, AA women have significantly poorer outcomes than EA women. In fact, the poorest outcomes in TNBC are for AA women with late-stage TNBC, having an abysmal five-year survival rate of only 14%. It is well established that a complex interplay of biologic (e.g., germline genetic features, oncogenic gene expression, and tumor microenvironment6 features) and non-biologic (e.g., socioeconomic disadvantages, societal stresses, and associated comorbidities such as obesity) factors underlie this disparity. As described above, our parent R37 focuses on molecular mechanisms of TNBC chemotherapy resistance. Notably, AA TNBC patients have higher rates of chemo-refractory disease and lower rates of chemo-sensitive disease compared to other ethnic groups7. The biological underpinnings of this disparity within TNBC are not understood. Our work has helped establish the key role of tumor cell mitochondrial structure and function in TNBC chemoresistance, and this has been recently affirmed by our collaborative teams’ large-scale patient8 and PDX9 datasets. However, this finding has not yet been placed into in the context of racial disparity. Based on our findings that mitochondria are key mediators of chemoresistance and based on the clear racial disparity of chemotherapy responses in TNBC, we hypothesize that racial disparity in mitochondrial structure and function contributes to the disparity of chemotherapeutic responses amongst TNBC patients. We will address this new hypothesis in the below specific aims. We expect that data generated within the scope of this proposed grant supplement will form a strong foundation for a full R01 proposal focused on mitochondrial network disparities between AA and EA TNBC, and we expect this knowledge will support mitochondria-targeting therapy development.