UCSF

Despite marked advancements in targeted therapeutics, breast cancer remains

the most diagnosed cancer and second leading cause of cancer-related death in

women in the United States. The triple-negative subtype of breast cancer (TNBC),

which lacks expression of the estrogen, progesterone and human epidermal growth

factor 2 receptors, has the highest proliferative and metastatic indices, and there are no

TNBC-specific therapies available in the clinic. Expression of the oncogenic

transcription factor MYC is elevated in TNBC. By its nature as a transcription factor, it is

challenging to drug MYC directly. An alternative strategy is a synthetic lethal approach

in which pathways are identified that are essential for MYC-overexpressing tumor cells,

but not normal cells. It has been shown that MYC alters metabolism during

tumorigenesis, however, its role in TNBC metabolism remains largely unexplored. In

addition, previous studies have largely been conducted in vitro, which may not

recapitulate metabolism found in vivo.

From targeted metabolomics on a transgenic mouse model of MYCoverexpressing

TNBC and RNA expression analysis of primary TNBC samples from

The Cancer Genome Atlas (TCGA), I identified fatty acid oxidation (FAO) as

dysregulated in TNBC. Using a variety of models, I demonstrated that MYCoverexpressing

TNBC has an increased bioenergetic reliance on FAO, and that

inhibition of FAO abrogates tumor growth. Given the interface that exists between

cancer cells and adipocytes in the breast, I examined whether tumor-adjacent adipose

tissue could be a source of fatty acids that fuel tumorigenesis. Studying tumors and

adjacent tissue from patient cohorts and mouse models, I found that lipolysis is

hyperactivated in breast tumor-adjacent adipocytes. I investigated the tumor-adipocyte

interface and found that gap junctions form between breast cancer cells and adipocytes

that transfer cAMP, a lipolysis-inducing signaling molecule, from tumor cells to

adipocytes. In addition, tumor-adipocyte gap junction formation requires connexin 31

(Cx31), the most upregulated connexin in the TCGA TNBC cohort, and Cx31 is

essential for tumor growth and activation of lipolysis. Thus, I have identified FAO and

tumor cell-adipocyte gap junctions as critical elements of TNBC tumorigenesis that may

serve as new therapeutic targets to treat this aggressive subset of breast cancer.