The Role of Annexin A6 in Triple-negative breast cancer metabolism and disease progression

The ability of cancer cells to alter their metabolism is one of the major mechanisms underlying therapeutic resistance in solid tumors, including the hard-to-treat triple-negative breast cancer (TNBC) subtype. Here, we report the synergism between Annexin A6 (AnxA6) and Lapatinib-resistance (Lap-R) in the context of metabolic reprogramming. Metabolic profiling of TNBC cell lines show extensive diversity amongst the proliferative basal-like (BSL) vs the highly motile mesenchymal-like (MSL) molecular subtypes. In this study, we demonstrate that down regulation of AnxA6 in AnxA6-, expressing and Lap-R cell lines attenuated mitochondrial respiration, glycolytic flux, and cellular ATP production capacity, diminishing the overall energy phenotype of the cell. Additionally, AnxA6-depletion altered lipid metabolism by decreasing lipid droplet accumulation, but enhancing the mitochondrial uptake and degradation of free fatty acids for ATP production via fatty acid oxidation (FAO). Our NMR-based metabolomics revealed that AnxA6 depleted and Lap-R TNBC cells rely on active amino acid metabolites and gluconeogenic precursors including alanine, glycine, and lactic acid to sustain their high proliferative rate. Collectively, these results demonstrate that the expression of AnxA6 underlies TNBC metabolic dependency and hence provide novel insights into the failure of EGFR-targeted therapies as therapeutic options for TNBC patients. © FASEB.