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Identification of Cyclin-dependent Kinase 1 Specific Phosphorylation Sites by an In Vitro Kinase Assay
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Identification of Cyclin-dependent Kinase 1 Specific Phosphorylation Sites by an In Vitro Kinase Assay

Published on: May 3, 2018

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CDK2-mediated site-specific phosphorylation of EZH2 drives and maintains triple-negative breast cancer

Lei Nie1, Yongkun Wei1, Fei Zhang1,2

  • 1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.

Nature Communications
|November 10, 2019
PubMed

Insights

Targeting cyclin-dependent kinase 2 (CDK2) or enhancer of zeste homolog 2 (EZH2) can convert triple-negative breast cancer (TNBC) to a tamoxifen-treatable form. Combination therapy with CDK2/EZH2 inhibitors and tamoxifen shows promise for TNBC treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Triple-negative breast cancer (TNBC) lacks key therapeutic targets like ERα, PR, and HER2, making it difficult to treat.
  • Cyclin E/cyclin-dependent kinase 2 (CDK2) phosphorylates enhancer of zeste homolog 2 (EZH2) at T416, a modification linked to cancer progression.

Purpose of the Study:

  • To investigate the role of EZH2 phosphorylation in TNBC development and explore therapeutic strategies.
  • To determine if inhibiting CDK2 or EZH2 can reverse the TNBC phenotype and restore hormone receptor expression.

Main Methods:

  • Transgenic expression of a phospho-mimicking EZH2 mutant (Ezh2T416D) in mouse mammary glands.
  • Utilizing HER2/Neu transgenic mice to study tumor reprogramming.
  • Employing pharmacological inhibitors of CDK2 and EZH2.
  • Assessing the efficacy of combination therapy with inhibitors and tamoxifen.

Main Results:

  • Transgenic expression of EZH2T416D induced TNBC phenotype in mouse mammary glands.
  • Coexpression of EZH2T416D converted HER2-driven luminal tumors to basal-like tumors.
  • Inhibition of CDK2 or EZH2 restored ERα expression, making TNBC cells responsive to tamoxifen.
  • Combined CDK2/EZH2 inhibition with tamoxifen suppressed tumor growth and improved survival in TNBC models.

Conclusions:

  • EZH2 phosphorylation at T416 plays a critical role in driving the TNBC phenotype.
  • Targeting CDK2 or EZH2 offers a strategy to re-sensitize TNBC to endocrine therapy.
  • Mechanism-based combination therapy with CDK2/EZH2 inhibitors and tamoxifen presents a potential new treatment approach for TNBC.

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