TMEM176B Regulates AKT/mTOR Signaling and Tumor Growth in Triple-Negative Breast Cancer
Chifei Kang,
Ran Rostoker,
Sarit Ben-Shumel,
Rola Rashed,
James Andrew Duty,
Deniz Demircioglu,
Irini M. Antoniou,
Lika Isakov,
Zila Shen-Orr,
Jose Javier Bravo-Cordero,
Nathan Kase,
Math P. Cuajungco,
Thomas M. Moran,
Derek LeRoith,
Emily Jane Gallagher
Affiliations
Chifei Kang
Division of Endocrinology, Diabetes and Bone Disease, Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, Box 1055, New York, NY 10029, USA
Ran Rostoker
Diabetes and Metabolism Clinical Research Center of Excellence, Clinical Research Institute at Rambam (CRIR) and the Faculty of Medicine, Technion, Rambam Medical Center, Haifa 31096, Israel
Sarit Ben-Shumel
Diabetes and Metabolism Clinical Research Center of Excellence, Clinical Research Institute at Rambam (CRIR) and the Faculty of Medicine, Technion, Rambam Medical Center, Haifa 31096, Israel
Rola Rashed
Diabetes and Metabolism Clinical Research Center of Excellence, Clinical Research Institute at Rambam (CRIR) and the Faculty of Medicine, Technion, Rambam Medical Center, Haifa 31096, Israel
James Andrew Duty
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Deniz Demircioglu
The Bioinformatic for Next Generation Sequencing (BiNGS) Core, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Irini M. Antoniou
Division of Endocrinology, Diabetes and Bone Disease, Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, Box 1055, New York, NY 10029, USA
Lika Isakov
Diabetes and Metabolism Clinical Research Center of Excellence, Clinical Research Institute at Rambam (CRIR) and the Faculty of Medicine, Technion, Rambam Medical Center, Haifa 31096, Israel
Zila Shen-Orr
Diabetes and Metabolism Clinical Research Center of Excellence, Clinical Research Institute at Rambam (CRIR) and the Faculty of Medicine, Technion, Rambam Medical Center, Haifa 31096, Israel
Jose Javier Bravo-Cordero
Division of Hematology and Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Nathan Kase
Division of Endocrinology, Diabetes and Bone Disease, Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, Box 1055, New York, NY 10029, USA
Math P. Cuajungco
Biological Science, California State University, Fullerton, CA 92831, USA
Thomas M. Moran
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Derek LeRoith
Division of Endocrinology, Diabetes and Bone Disease, Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, Box 1055, New York, NY 10029, USA
Emily Jane Gallagher
Division of Endocrinology, Diabetes and Bone Disease, Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, Box 1055, New York, NY 10029, USA
TMEM176B is a member of the membrane spanning 4-domains (MS4) family of transmembrane proteins, and a putative ion channel that is expressed in immune cells and certain cancers. We aimed to understand the role of TMEM176B in cancer cell signaling, gene expression, cell proliferation, and migration in vitro, as well as tumor growth in vivo. We generated breast cancer cell lines with overexpressed and silenced TMEM176B, and a therapeutic antibody targeting TMEM176B. Proliferation and migration assays were performed in vitro, and tumor growth was evaluated in vivo. We performed gene expression and Western blot analyses to identify the most differentially regulated genes and signaling pathways in cells with TMEM176B overexpression and silencing. Silencing TMEM176B or inhibiting it with a therapeutic antibody impaired cell proliferation, while overexpression increased proliferation in vitro. Syngeneic and xenograft tumor studies revealed the attenuated growth of tumors with TMEM176B gene silencing compared with controls. We found that the AKT/mTOR signaling pathway was activated or repressed in cells overexpressing or silenced for TMEM176B, respectively. Overall, our results suggest that TMEM176B expression in breast cancer cells regulates key signaling pathways and genes that contribute to cancer cell growth and progression, and is a potential target for therapeutic antibodies.
