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

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

TMEM176B is a member of the membrane spanning 4-domains (MS4) family of transmem-brane 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 pro-liferation, 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 over-expression 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.

Original languageEnglish
Article number3430
JournalCells
Volume10
Issue number12
DOIs
StatePublished - Dec 2021

Keywords

  • AKT/mTOR signaling
  • Calcium channel
  • RNA-seq
  • TMEM176B
  • Therapeutic antibodies
  • Triple negative breast cancer

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