Tumor cell-adipocyte gap junctions activate lipolysis in breast cancer

Abstract During tumorigenesis, a heterotypic interface exists between cancer and stromal cells that can both support and repress tumor growth. In the breast, 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, patient-derived xenografts and mouse models, we show that lipolysis and lipolytic signaling are activated in NAT. We investigated the tumor-adipocyte interface and find that functional gap junctions form between breast cancer cells and adipocytes. As a result, cAMP, a critical lipolysis-inducing signaling molecule, is transferred from breast cancer cells to adipocytes and activates lipolysis in a gap junction-dependent manner. We found that gap junction formation depends 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. One sentence summary Gap junctions between breast cancer cells and adipocytes transfer cAMP and activate lipolysis in the breast tumor microenvironment.