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Identification of mTORC2 as a necessary component of HRG/ErbB2-dependent cellular transformation

Miao-chong J Lin1, Katherine S Rojas1, Richard A Cerione2

  • 1Authors' Affiliation: Department of Molecular Medicine, Cornell University, Ithaca, New York.

Molecular Cancer Research : MCR
|March 12, 2014
PubMed
Abstract

Insights

Targeting mTORC2 shows promise for treating HER2-positive breast cancer driven by heregulin. This study reveals mTORC2

Area of Science:

  • Molecular Oncology
  • Signal Transduction
  • Breast Cancer Research

Background:

  • Overexpression of HER2/ErbB2 (ERBB2) and heregulin (HRG/NRG1) drives breast cancer progression and poor prognosis.
  • While ErbB2 inhibitors are crucial, clinical resistance necessitates understanding HRG/ErbB2-induced tumorigenesis mechanisms.
  • HRG promotes anchorage-independent growth, a hallmark of cancer, more potently than EGF.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying HRG/ErbB2-induced breast cancer.
  • To investigate the role of mTORC1 and mTORC2 in HRG-mediated breast cancer cell transformation.
  • To evaluate the therapeutic potential of targeting mTORC2 in HRG/ErbB2-dependent breast cancer.

Main Methods:

  • Assessed HRG-induced anchorage-independent cell growth and compared it with EGF.
  • Investigated the necessity of phosphoinositide 3-kinase and mTORC1 activation for cell transformation.
  • Utilized mTOR inhibitors (rapamycin, INK-128) to study signaling pathways and the role of mTORC2.
  • Examined the impact of Rictor (RICTOR) depletion on mTORC1 activation and cellular transformation.

Main Results:

  • HRG significantly promoted anchorage-independent breast cancer cell growth.
  • HRG-dependent activation of phosphoinositide 3-kinase and mTORC1 was essential for cell transformation.
  • mTORC2 plays a critical role in regulating the AKT/TSC2/mTORC1 axis by influencing AKT phosphorylation.
  • Depletion of Rictor (RICTOR), a key mTORC2 component, inhibited mTORC1 activation and HRG-mediated transformation.

Conclusions:

  • mTORC2 is a crucial regulator in HRG/ErbB2-dependent breast cancer.
  • Targeting mTORC2 presents a potential therapeutic strategy for HRG/ErbB2-induced breast cancers.
  • Understanding the mTORC2 pathway is vital for overcoming resistance to current therapies.

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