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Methylation of Notch3 modulates chemoresistance via P-glycoprotein

Xiaoting Gu1, Yangfan Lu1, Dongxu He2

  • 1School of Pharmaceutical Sciences, Jiangnan University, 1800 Lihu Rd, Wuxi, Jiangsu 214122, China.

European Journal of Pharmacology
|November 7, 2016
PubMed

Insights

Epigenetic silencing of the Notch3 gene via DNA hypermethylation inactivates this tumor suppressor in adriamycin-resistant breast cancer cells. This leads to increased P-glycoprotein expression, contributing to drug resistance.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Epigenetics

Background:

  • Chemoresistance in breast cancer is a significant clinical challenge.
  • DNA methylation patterns are altered in chemoresistant cells, affecting gene expression and cellular characteristics.
  • Understanding the epigenetic mechanisms underlying drug resistance is crucial for developing effective therapies.

Purpose of the Study:

  • To investigate the role of DNA methylation in adriamycin resistance in human breast cancer cells (MCF-7/ADM).
  • To identify specific genes affected by epigenetic alterations in chemoresistant cells.
  • To elucidate the relationship between gene methylation, tumor suppressor gene inactivation, and drug efflux pump expression.

Main Methods:

  • Comparative analysis of gene expression and DNA methylation in adriamycin-resistant (MCF-7/ADM), paclitaxel-resistant (MCF-7/PTX), and wild-type (MCF-7) breast cancer cells.
  • Investigation of epigenetic silencing of the tumor-suppressor gene Notch3 through DNA hypermethylation.
  • Assessment of the regulatory relationship between Notch3 and the drug efflux pump P-glycoprotein.

Main Results:

  • Global gene expression and DNA methylation profiles of MCF-7/ADM cells closely resemble MCF-7/PTX cells and differ significantly from wild-type MCF-7 cells.
  • The tumor-suppressor gene Notch3 was found to be epigenetically silenced by DNA hypermethylation in MCF-7/ADM cells.
  • Notch3 negatively regulates P-glycoprotein, which was highly expressed in MCF-7/ADM cells, indicating Notch3 inactivation contributes to its upregulation.

Conclusions:

  • DNA hypermethylation of the Notch3 gene is a key mechanism for its inactivation in adriamycin-resistant breast cancer cells.
  • Inactivation of Notch3 leads to the activation and high expression of the P-glycoprotein drug efflux pump.
  • These findings highlight the critical role of epigenetic modifications in mediating chemoresistance and suggest potential therapeutic targets.
Keywords:
Breast cancerChemoresistanceDNA methylationNotch3P-glycoprotein

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