Rheb1-Independent Activation of mTORC1 in Mammary Tumors Occurs through Activating Mutations in mTOR

Bin Xiao, Dongmei Zuo, Alison Hirukawa, Robert D. Cardiff, Richard Lamb, Nahum Sonenberg, William J. Muller

Research output: Contribution to journalArticle

Abstract

Mechanistic target of rapamycin complex 1 (mTORC1) is a master modulator of cellular growth, and its aberrant regulation is recurrently documented within breast cancer. While the small GTPase Rheb1 is the canonical activator of mTORC1, Rheb1-independent mechanisms of mTORC1 activation have also been reported but have not been fully understood. Employing multiple transgenic mouse models of breast cancer, we report that ablation of Rheb1 significantly impedes mammary tumorigenesis. In the absence of Rheb1, a block in tumor initiation can be overcome by multiple independent mutations in Mtor to allow Rheb1-independent reactivation of mTORC1. We further demonstrate that the mTOR kinase is indispensable for tumor initiation as the genetic ablation of mTOR abolishes mammary tumorigenesis. Collectively, our findings demonstrate that mTORC1 activation is indispensable for mammary tumor initiation and that tumors acquire alternative mechanisms of mTORC1 activation.

Original languageEnglish (US)
Article number107571
JournalCell Reports
Volume31
Issue number4
DOIs
StatePublished - Apr 28 2020

Keywords

  • breast
  • cancer
  • mTOR
  • mutation
  • Rheb
  • tumorigenesis

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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