Abstract 2398: Tumor cell-adipocyte gap junctions activate lipolysis in breast cancer
Authors: Camarda Roman , Williams Jeremy , Malkov Serghei , Zimmerman Lisa J. , Manning Suzanne , Aran Dvir , Beardsley Andrew , Mark Daniel Van de , Haren Jeffrey van , Chen Yong , Berdan Charles , Louie Sharon , Mahieu Celine , Winkler Juliane , Willey Elizabeth , Gagnon John D. , Shinoda Kosaku , Ansel K. Mark , Werb Zena , Nomura Daniel C. , Kajimura Shingo , Wittmann Torsten , Butte Atul J. , Sanders Melinda E. , Liebler Daniel C. , Krings Gregor , Shepherd John A. , Goga Andrei 
Published: August 2018

Abstract
During mammary tumorigenesis, a cell-cell interface exists between adipocytes and cancer cells. Several studies have demonstrated that breast tumor cells can secrete cytokines that induce lipolysis in adjacent adipocytes. However, evidence of tumor-adjacent lipolysis in clinical samples has been lacking. We therefore assayed for lipolysis in normal tissue adjacent to breast tumors (NAT) using (1) the three-component breast composition measure, a radiographic imaging method derived from dual-energy mammography that allows lipid content of a tissue to be quantified, on breast tumors and NAT from 46 patients, (2) a publically available dataset of gene expression in primary breast tumors and NAT from 9 patients, (3) laser capture microdissection and proteomics on primary breast tumors, stroma and NAT from 75 patients, and (4) immunoblot analysis of NAT from several patient-derived and transgenic mouse models of breast cancer. We found strong evidence in all cases that lipolysis is activated in breast cancer-adjacent adipose tissue. We next set out to model the breast cancer-adipocyte interface and determine the contribution of cell-cell contact to induced lipolysis. Gap junctions are cell-cell junctions formed by proteins called connexins, which are known to transport a variety of small molecules (&lt;1kD) including cAMP, a critical pro-lipolytic signaling molecule. Using established dye transfer assays, we determined that gap junctions form between breast cancer cells, and between breast cancer cells and adipocytes. Using biochemical assays, we demonstrated that cAMP is a substrate of breast cancer cell gap junctions, that transfer of cAMP from breast cancer cells to adipocytes occurs, and that breast cancer cells activate lipolytic signaling, all in a gap junction-dependent manner. Finally, we found that gap junction communication in this context is dependent upon connexin 31 (Cx31), and we establish the importance of Cx31 for breast tumor growth and activation of lipolysis in tumor-adjacent adipose tissue in vivo.
Citation Format: Roman Camarda, Jeremy Williams, Serghei Malkov, Lisa J. Zimmerman, Suzanne Manning, Dvir Aran, Andrew Beardsley, Daniel Van de Mark, Jeffrey van Haren, Yong Chen, Charles Berdan, Sharon Louie, Celine Mahieu, Juliane Winkler, Elizabeth Willey, John D. Gagnon, Kosaku Shinoda, K. Mark Ansel, Zena Werb, Daniel C. Nomura, Shingo Kajimura, Torsten Wittmann, Atul J. Butte, Melinda E. Sanders, Daniel C. Liebler, Gregor Krings, John A. Shepherd, Andrei Goga. Tumor cell-adipocyte gap junctions activate lipolysis in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2398.