Compared to hormone regulated/responsive breast cancers (BCs), basal or triple negative BC (TNBC) patients suffer a worse overall survival, a significantly shorter disease-free survival after treatment, and a shorter post-recurrence survival. This comparatively bad prognosis of TNBC is mostly caused by the limited understanding of its driver signaling pathways, therapeutic targets and a lack of the proper selection of patients for a target-specific therapy. Although there is ample evidence of unique characteristics of TNBC, clinical benefit from currently available targeted therapies/approaches is limited, and new therapeutic strategies are urgently needed to reduce its severity. Recent diet-intervention studies including the Women's Intervention Nutrition Study (WINS) reports show that deaths of women with TNBC were reduced when they followed a reduced dietary-fat-intake program. This death reduction rate is better than any of the currently available treatment options for TNBC. This highlights the relevance of fat and fat metabolism in TNBC. The proposed study will focus on this important aspect of TNBC. Mitochondria are the cellular powerhouses and play an important role in the fat metabolism. Proto-oncogene c-Src (Src) is one of the most commonly upregulated oncopathways in TNBC. Src inhibitors like dasatinib are one of the suggested therapeutic options for TNBC. However, clinical studies showed only partial success in treatment with single drug that target Src. Thus, decision on which patients should be selected for Src-directed therapies and what combination therapy should be administered will be important for the clinical success of these agents in TNBC. We and others have recently reported that aggressive TNBC largely depends on energy from mitochondrial fatty acid ?-oxidation (FAO). Moreover, we discovered that FAO plays significant role in the activation of Src-oncopathway in TNBC. Here, we will investigate the role of high-fat-diet (HFD)-mediated FAO in maintaining the high Src activity in TNBC. Since activated Src is also known to regulate proteins in the mitochondrial electron transport chain (ETC), we will evaluate the significance of activated Src in maintaining the HFD-mediated FAO and mitochondrial activity in TNBC as a feed-forward mechanism. We will use TNBC patient-derived xenografts (PDXs) to understand this mechanism. Most of these PDXs have already been characterized at histologic, transcriptomic, proteomic, and genomic levels, and showed comparable treatment responses as those observed clinically. Thus, outcome from this study can provide important preliminary information on the role of diet in the prevention and management of Src-regulated TNBC. This pilot project will also allow us to predict suitable combination therapies that are relevant in the management of TNBC patients with metabolism- regulated, Src-driven TNBC. Finally, this study will have significant impact on the selection of a subgroup of TNBC patients, who are currently suffering from limited targeted therapies and resistance development to current treatment options, for Src-targeted therapy.
We have discovered the critical role of mitochondrial reprogramming to fatty acid oxidation (FAO) in the regulation of c-Src cancer pathway in triple negative breast cancer (TNBC). This project will understand the significance of high-fat-diet (HFD) in the activation of c-Src pathway in TNBC using our well- characterized TNBC patient-derived xenograft (PDX) models. Using metabolomic and biochemical approaches, we will understand the HFD-regulated mitochondrial function in TNBC PDX and the role of Src in HFD-altered mitochondrial function.
