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mTOR signaling feedback modulates mammary epithelial differentiation and restrains invasion downstream of PTEN loss

Susmita Ghosh1, Lidenys Varela, Akshay Sood

  • 1Department of Pathology, Johns Hopkins University, Baltimore, MD, USA.

Cancer Research
|June 19, 2013
PubMed

Insights

PTEN loss in cancer can paradoxically promote tumor invasion by inhibiting mTOR signaling, which normally suppresses invasion. This suggests mTOR inhibitors may be harmful in PTEN-deficient tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • Negative feedback circuits regulate oncogenic signaling pathways, and their disruption is a common cause of drug resistance in tumors.
  • The role of these feedback pathways in cellular differentiation and morphogenesis within a specific genetic context remains unclear.

Purpose of the Study:

  • To investigate the role of mTOR-mediated negative feedback in PTEN inactivation within benign mammary organotypic cultures.
  • To understand the impact of PTEN loss on differentiation, morphogenesis, and epithelial invasion.

Main Methods:

  • Utilized isogenic benign mammary organotypic cultures and MCF10A cells with and without PTEN deletion.
  • Analyzed ex vivo murine cell cultures to assess signaling pathways and cellular responses.
  • Investigated the mechanistic link between mTOR inhibition, PTEN loss, and epithelial invasion.

Main Results:

  • Short-term PTEN loss promoted basal-like differentiation and repressed nuclear hormone receptor expression via mTOR signaling.
  • PTEN inactivation unexpectedly inhibited growth factor-induced epithelial invasion.
  • mTOR-mediated signaling feedback was essential and sufficient for inhibiting epithelial invasion following PTEN inactivation.
  • mTOR inhibition promoted EGF-mediated epithelial invasion by upregulating EGF receptor, SRC tyrosine kinase, and PI3K signaling.

Conclusions:

  • PTEN loss and subsequent mTOR inhibition have significant, clinically relevant consequences, including altered hormone/growth factor responsiveness and promotion of epithelial invasion.
  • mTOR inhibitor therapy might be ineffective or even detrimental in tumors with PTEN loss.
  • Findings warrant further investigation into mTOR inhibitor efficacy in PTEN-deficient cancers.

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