Tumor cell-adipocyte gap junctions activate lipolysis and are essential for breast tumorigenesis

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 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. 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; a fundamentally new mechanism of lipolysis activation in adipocytes. We find 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.