The MYC oncogene is overexpressed in some of the most aggressive and difficult to treat human cancers, including receptor triple-negative breast cancers (TNBCs), as well as high-grade lymphomas, aggressive subtypes of liver, head and neck and pediatric cancers. MYC overexpression induces a highly malignant state, at least in part, by reprogramming tumor metabolism. We and others have instead sought to exploit MYC driven processes that can be targeted. Using conditional transgenic tumor models we have uncovered new metabolic dependencies of MYC-driven cancers. While many cancer types upregulate fatty acid synthesis (FAS), we recently discovered that most TNBCs preferentially utilize a metabolic program of fatty acid oxidation (FAO) to sustain tumor proliferation and survival. Blocking FAO is a potentially new therapeutic target for treating aggressive breast and liver cancers.
During tumorigenesis, interactions between cancer and stromal cells that can both support and repress tumor growth. In the mammary gland, studies have demonstrated a pro-tumorigenic role for adipocytes. However, the molecular mechanisms by which breast cancer cells coopt adipocytes remain elusive. Studying breast tumors and normal adjacent tissue (NAT) from several patient cohorts and mouse models, we show that lipolysis and lipolytic signaling are activated in NAT. We investigate the tumor-adipocyte interface and find that functional gap junctions form between breast cancer cells and adipocytes. We establish that cAMP, a critical pro-lipolytic signaling molecule, is transferred from breast cancer cells to adipocytes to activate lipolytic signaling in a gap junction-dependent manner. Finally, we found that gap junction formation is dependent upon connexin 31 (Cx31), and that Cx31 is essential for breast tumor growth and activation of lipolysis in vivo. Thus, direct tumor cell-adipocyte interaction is critical for tumorigenesis, and may serve as a new therapeutic target in breast cancer.