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Updated: Nov 12, 2025

Integration of Bioinformatics Approaches and Experimental Validations to Understand the Role of Notch Signaling in Ovarian Cancer
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NOTCH and EZH2 collaborate to repress PTEN expression in breast cancer

Kyrie Pappas1,2,3,4, Tiphaine C Martin1,2, Andrew L Wolfe1,2,5

  • 1Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Communications Biology
|March 22, 2021
PubMed

Insights

PTEN tumor suppressor transcript is often lost in breast cancer. NOTCH and EZH2 alterations drive PTEN repression, contributing to poor prognosis, but PTEN expression can be restored with inhibitors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Downregulation of the PTEN tumor suppressor transcript is frequent in breast cancer, particularly triple-negative breast cancer (TNBC), and is associated with poor prognosis.
  • PTEN expression is typically decreased in breast tumors compared to adjacent normal tissues, while EZH2 (Enhancer of Zeste Homolog 2) expression is increased.

Purpose of the Study:

  • To investigate the relationship between EZH2, NOTCH signaling, and PTEN expression in breast cancer.
  • To elucidate the mechanism by which PTEN repression occurs and identify potential therapeutic targets.

Main Methods:

  • Comparative analysis of PTEN and EZH2 expression in breast tumors versus normal tissues.
  • Correlation studies of EZH2 and PTEN expression in large breast cancer cohorts.
  • Investigation of NOTCH alterations (mutations, fusions) and their association with EZH2 and PTEN levels.
  • Experimental validation of PTEN repression mechanism involving NOTCH and EZH2.
  • Assessment of therapeutic interventions including EZH2 and gamma-secretase inhibitors, and gene knockdown.

Main Results:

  • PTEN expression is decreased and EZH2 expression is increased in nearly all breast tumors compared to normal ducts.
  • EZH2 inversely correlates with PTEN expression in breast cancer cohorts.
  • NOTCH alterations are frequent in tumors with high EZH2 expression and are associated with decreased PTEN.
  • NOTCH (NOTCH1/2) and EZH2 cooperate to transcriptionally repress PTEN in a subset of breast cancers.
  • PTEN expression can be restored by inhibiting EZH2 or NOTCH signaling pathways.

Conclusions:

  • NOTCH and EZH2 alterations drive PTEN transcriptional repression, contributing to poor prognosis in a subset of breast cancers.
  • Targeting EZH2 or NOTCH signaling pathways represents a potential therapeutic strategy for restoring PTEN expression and improving outcomes in these patients.

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