Tumor cell-adipocyte gap junctions activate lipolysis and contribute to breast tumorigenesis
Abstract
Abstract A pro-tumorigenic role for adipocytes has been identified in breast cancer, and reliance on fatty acid catabolism found in aggressive tumors. The molecular mechanisms by which tumor cells coopt neighboring adipocytes, however, remain incompletely understood. Here, we describe a direct interaction linking tumorigenesis to adjacent adipocytes. We examine breast tumors and their normal adjacent tissue from several patient cohorts, patient-derived xenografts, and mouse models, and find that lipolysis and lipolytic signaling are activated in neighboring adipose tissue. We find that functional gap junctions form between breast cancer cells and adipocytes. As a result, cAMP is transferred from breast cancer cells to adipocytes and activates lipolysis in a gap junction-dependent manner. We find that connexin 31 ( GJB3 ) promotes receptor triple negative breast cancer growth and activation of lipolysis in vivo. Thus, direct tumor cell-adipocyte interaction contributes to tumorigenesis and may serve as a new therapeutic target in breast cancer.
Article Details
Authors (33)
Jeremy Williams
Roman Camarda
Serghei Malkov
Lisa J. Zimmerman
Suzanne Manning
Dvir Aran
Andrew Beardsley
Daniel Van de Mark
Rachel Nakagawa
Yong Chen
Charles Berdan
Sharon M. Louie
Celine Mahieu
Daphne Superville
Juliane Winkler
Elizabeth Willey
Erica J. Hutchins
John D. Gagnon
Seda Kilinc Avsaroglu
Kosaku Shinoda
Matthew Gruner
Hiroshi Nishida
K. Mark Ansel
Zena Werb
Daniel K. Nomura
Shingo Kajimura
Atul J. Butte
Melinda E. Sanders
Daniel C. Liebler
Hope S. Rugo
City of Hope Comprehensive Cancer Center, Duarte, CA
Gregor Krings
John A. Shepherd
Andrei Goga