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ZEB1 confers chemotherapeutic resistance to breast cancer by activating ATM

Xiang Zhang1, Zhen Zhang2, Qing Zhang2

  • 1Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.

Cell Death & Disease
|January 21, 2018
PubMed

Insights

High ZEB1 expression in breast cancer predicts poor response to chemotherapy by promoting DNA repair. This suggests ZEB1 is a key factor in developing chemoresistance in breast cancer patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Zinc finger E-box binding homeobox 1 (ZEB1) is implicated in breast cancer progression.
  • The role of ZEB1 in chemoresistance remains unclear.

Purpose of the Study:

  • To investigate the role of ZEB1 in breast cancer chemoresistance.
  • To elucidate the molecular mechanisms underlying ZEB1-mediated chemoresistance.

Main Methods:

  • Analysis of ZEB1 expression in human breast cancer specimens.
  • In vitro studies using breast cancer cell lines with ectopic ZEB1 expression.
  • In vivo studies using a nude mouse xenograft model.
  • Investigation of molecular interactions involving ZEB1, Bcl-xL, cyclin D1, ATM, and DNA repair pathways.

Main Results:

  • High ZEB1 expression correlates with poor response to chemotherapy in breast cancer patients.
  • ZEB1 expression is positively associated with Bcl-xL and cyclin D1.
  • Ectopic ZEB1 expression reduces sensitivity to epirubicin (EPI) in vitro and in vivo.
  • ZEB1 activates ATM kinase expression via a ZEB1/p300/PCAF complex, enhancing DNA repair.

Conclusions:

  • ZEB1 is a critical determinant of chemoresistance in breast cancer.
  • ZEB1 promotes chemoresistance by enhancing DNA damage repair through ATM activation.
  • Targeting ZEB1 may represent a therapeutic strategy to overcome chemotherapy resistance.

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