RACIAL DISPARITY IN THE ENERGY DEPENDENCY OF TRIPLE NEGATIVE BREAST CANCER

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Abstract: Breast cancer (BC) statistics over the years have repeatedly shown that while BC incidence is higher in Caucasian (CA) women, death due to BC is higher in African American (AA) women. Importantly, AA patients are more likely to be diagnosed of BC at a younger age and have a higher probability of developing aggressive triple negative (TN) BC. AA TNBC is also diagnosed with a more advanced stage of the disease compared to CA women. This project plans to address the differential mitochondrial reprogramming between AA and CA TNBC patients. Considering our previous publication and preliminary data, here we use modulation in the activation of Src oncopathway as a major readout of metabolic reprogramming. We have previously showed that TNBC cells have high energy dependency to fatty acid β-oxidation (FAO) and FAO is an important determinant of Src activation by autophosphorylation at its Y419 site. However, our recent analyses suggest that this dependency is mostly restricted to CA TNBC. AA TNBC cells are not responding to FAO inhibitors as observed with most of the CA TNBC, and FAO inhibitors do not decrease Src autophosphorylation in AA TNBC. Further analysis suggest that, even though Src depends on Krebs cycle (TCA) activity in both AA and CA TNBC cells, the source of acetyl-CoA for TCA is significantly different between these two groups. Thus, this project is planning to address the disparity in energy dependency between AA and CA TNBC tumors. Our preliminary data also suggest that increased Myc, pyruvate carboxylase (PC) and argininosuccinate synthase 1 (ASS1) activities in AA TNBC are critical in their enhanced arginine pathway. We have also proposed a translational aim to understand the role of TCA inhibitors in the therapeutic response of AA TNBC to Src inhibitors. Thus, this project will provide critical information regarding the energy dependency and onco- pathway activation in AA TNBC. The project involves experiments utilizing several AA and CA TNBC cell lines, patient-derived xenografts (PDX) models as well as deidentified BC tissues obtained from AA and CA TNBC patients. This project also involves genomic, proteomic, metabolomic, bioinformatic and clinical approaches including in vivo studies in animal models. Overall, this study will provide an important scientific mechanism behind the racial disparity of energy dependency and regulation of onco-pathways in AA TNBC patients. The outcome can support in the development of race-specific combination therapies for the management of aggressive TNBC.