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Breast Cancer Research and Treatment

, Volume 127, Issue 2, pp 417–427 | Cite as

Estrogen receptor beta decreases survival of p53-defective cancer cells after DNA damage by impairing G2/M checkpoint signaling

  • Christoforos G. Thomas
  • Anders Strom
  • Karolina Lindberg
  • Jan-Ake Gustafsson
Preclinical study

Abstract

Estrogen receptor beta (ERβ) inhibits proliferation in different cellular systems by regulating components of the cell cycle machinery. Eukaryotic cells respond to DNA damage by arresting in G1, S, or G2 phases of the cell cycle to initiate DNA repair. Most tumor cells due to disruptions in the p53-dependent G1 pathway are dependent on S-phase and G2/M checkpoints to maintain genomic integrity in response to DNA damage. We report that induction of ERβ expression causes abrogation of the S-phase, and the Chk1/Cdc25C-mediated G2/M checkpoints after cisplatin and doxorubicin exposure in p53-defective breast cancer cells but not in p53 wild-type mammary cells. This impairment of DNA damage response that involves BRCA1 downregulation and caspase-2 activation results in mitotic catastrophe and decreased cancer cell survival. These results indicate that in cancers where p53 is defective, assessment of the presence of ERβ may be of predictive value for the successful response to chemotherapy.

Keywords

Estrogen receptor beta p53 BRCA1 DNA damage response Cancer cells Caspase-2 

Abbreviations

BRCA

Breast cancer susceptibility protein

Cis

Cisplatin

DBD

DNA binding domain

DCC

Dextran-coated charcoal

Dox

Doxorubicin

ERα

Estrogen receptor alpha

ERβ

Estrogen receptor beta

FACS

Fluorescence-activated cell sorter

FCS

Fetal calf serum

MEFs

Mouse embryo fibroblasts

PI

Propidium iodide

PBS

Phosphate-buffered saline

pHH3

Phospho-histone H3

Notes

Acknowledgments

We thank Tassos Diadmimopoulos, Fotis Nikolos and Gayani Rajapaksa for technical help and Aurélie Escande for providing us with the ERβ-expressing HeLa cells. We thank Margaret Warner for critically reading the manuscript. This study was supported by the Swedish Cancer Society and the Welch Foundation.

Conflict of interest statement

The authors declare no conflict of interest.

Supplementary material

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Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • Christoforos G. Thomas
    • 1
  • Anders Strom
    • 1
  • Karolina Lindberg
    • 2
  • Jan-Ake Gustafsson
    • 1
    • 2
  1. 1.Center for Nuclear Receptors and Cell Signaling, Department of Biology and BiochemistryUniversity of HoustonHoustonTexas
  2. 2.Department of Biosciences and NutritionKarolinska InstituteHuddingeSweden

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