Metabolic requirements necessitate microenvironmental crosstalk in breast cancer

Despite marked advancements in targeted therapeutics, breast cancer remainsthe most diagnosed cancer and second leading cause of cancer-related death inwomen in the United States. The triple-negative subtype of breast cancer (TNBC),which lacks expression of the estrogen, progesterone and human epidermal growthfactor 2 receptors, has the highest proliferative and metastatic indices, and there are noTNBC-specific therapies available in the clinic. Expression of the oncogenictranscription factor MYC is elevated in TNBC. By its nature as a transcription factor, it ischallenging to drug MYC directly. An alternative strategy is a synthetic lethal approachin which pathways are identified that are essential for MYC-overexpressing tumor cells,but not normal cells. It has been shown that MYC alters metabolism duringtumorigenesis, however, its role in TNBC metabolism remains largely unexplored. Inaddition, previous studies have largely been conducted in vitro, which may notrecapitulate metabolism found in vivo.From targeted metabolomics on a transgenic mouse model of MYCoverexpressingTNBC and RNA expression analysis of primary TNBC samples fromThe Cancer Genome Atlas (TCGA), I identified fatty acid oxidation (FAO) asdysregulated in TNBC. Using a variety of models, I demonstrated that MYCoverexpressingTNBC has an increased bioenergetic reliance on FAO, and thatinhibition of FAO abrogates tumor growth. Given the interface that exists betweencancer cells and adipocytes in the breast, I examined whether tumor-adjacent adiposetissue could be a source of fatty acids that fuel tumorigenesis. Studying tumors andadjacent tissue from patient cohorts and mouse models, I found that lipolysis ishyperactivated in breast tumor-adjacent adipocytes. I investigated the tumor-adipocyteinterface and found that gap junctions form between breast cancer cells and adipocytesthat transfer cAMP, a lipolysis-inducing signaling molecule, from tumor cells toadipocytes. In addition, tumor-adipocyte gap junction formation requires connexin 31(Cx31), the most upregulated connexin in the TCGA TNBC cohort, and Cx31 isessential for tumor growth and activation of lipolysis. Thus, I have identified FAO andtumor cell-adipocyte gap junctions as critical elements of TNBC tumorigenesis that mayserve as new therapeutic targets to treat this aggressive subset of breast cancer