UCSF

Tumors display altered metabolism, often reflective of their microenvironment. In many cases including breast cancer, the invasive tumor front borders adipocytes. Reliance on mitochondrial fatty acid oxidation (FAO) has been observed in aggressive receptor ‘triple-negative’ breast cancers (TNBC), but the adaptations that permit elevated FAO, and the molecular mechanisms by which tumors coopt adjacent adipocytes for growth, remain elusive. The oncogene MYC dysregulates a range of cellular programs, including metabolism; MYC expression is elevated in most TNBC, and linked to increased FAO. To delineate alterations facilitating FAO in TNBC, I examined fatty acid binding proteins (FABP) thought to traffic FA to the mitochondria. Prior work identified FABP5 elevation in patient TNBC and a model of MYC-driven breast cancer. I observed increased FABP5 transcription in TN compared to ‘receptor-positive’ patient-derived cell lines, yet elevation across MYC-low and -high TNBC suggested levels are not solely MYC-regulated. Treating MYC-driven breast cancer cells with an FABP5/7 inhibitor caused lipid accumulation and impaired proliferation, but I found no growth defect after FABP5 knockout. While compensation by other FABPs may complicate knockout studies, specific inhibitors for FABP5 and other FAM targets are in clinical development. Despite evidence indicating reliance on FAO in TNBC, the source of FA fueling aggressive tumor growth is unclear. I next described a direct interaction linking cancer cell-adipocyte contact to tumor progression. Examining breast tumors and normal adjacent tissue from patient cohorts, patient-derived xenografts and mouse models, we observed activation of lipolysis and lipolytic signaling in neighboring adipose tissue. Using cancer cell adipocyte co-cultures, I found that functional gap junctions (GJ), small intercellular channels, form and permit cAMP transfer from breast cancer cells to adipocytes, activating lipolysis in a GJ-dependent manner. We identified connexin 31 (GJB3) as a promoter of in vivo TNBC growth and activation of adjacent lipolysis, or FA release. Our findings indicate a pro-tumorigenic role for direct tumor cell-adipocyte interactions. These studies reveal that TNBC dysregulate tumoral lipid metabolism and stimulate altered FAM in surrounding tissue.