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

doi:10.1016/j.celrep.2020.107571

Bin Xiao, Dongmei Zuo + Show 5 more

Open Access

https://doi.org/10.1016/j.celrep.2020.107571

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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.

Highlights

Mammary tumorigenesis is a multistep evolutionary process involving the selection for genetic or epigenetic alternations that allow the preneoplastic epithelial cell population to subvert barriers to uncontrolled growth and survival, correlating within progression through a series of pathologic stages (Liggett and Sidransky, 1998; Sherr and McCormick, 2002; Wright and Shay, 2000; Visvader, 2011)
Mammary Ablation of Rheb1 Delays Mammary Tumorigenesis To evaluate the involvement of Mechanistic target of rapamycin complex 1 (mTORC1) signaling in mammary tumor initiation, we used mammary epithelial-specific conditional gene targeting to delete the upstream activator Rheb1 in two GEMMs representative of the ErbB2-positive and luminal B breast cancer subtype (Herschkowitz et al, 2007)
We evaluated the immediate effects of Rheb1 ablation on the early stages of mammary tumorigenesis by examining the mammary glands of Rheb1fl/fl MIC mice following 4 and 14 days of Dox induction

Summary

Introduction

Mammary tumorigenesis is a multistep evolutionary process involving the selection for genetic or epigenetic alternations that allow the preneoplastic epithelial cell population to subvert barriers to uncontrolled growth and survival, correlating within progression through a series of pathologic stages (Liggett and Sidransky, 1998; Sherr and McCormick, 2002; Wright and Shay, 2000; Visvader, 2011). The multistep evolutionary nature of mammary tumor initiation is closely recapitulated by genetically engineered mouse models (GEMMs) of breast cancer (Andrechek et al, 2003). Mammary-specific expression of the oncogenic receptor tyrosine ErbB2 or the polyomavirus middle T antigen (PyV mT) is sufficient to drive tumorigenesis through a series of premalignant stages that culminate in the formation of metastatic mammary tumors (Guy et al, 1992a, 1992b, 1996; Schade et al, 2013). Specific functions of mTORC1 include stimulation of protein synthesis through phosphorylation of p70 S6 kinases 1 and 2 and the eukaryotic initiation factor 4E-binding protein

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