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Breast Cancer Research
Published in: Breast Cancer Research 1/2006

Open Access 01-02-2005 | Research article

New role for nuclear hormone receptors and coactivators in regulation of BRCA1-mediated DNA repair in breast cancer cell lines

Authors: David L Crowe, Matt K Lee

Published in: Breast Cancer Research | Issue 1/2006

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Abstract

Introduction

The breast cancer susceptibility gene BRCA1 is involved in the repair of double-strand breaks induced by ionizing radiation and chemotherapy drugs. BRCA1 interacts with coactivators such as p300 and CREB-binding protein (CBP) to activate target gene transcription. Estrogen and retinoic acid receptors (ER and RAR) also require coactivator proteins for their ligand-dependent functions. Few studies have suggested a role for nuclear hormone receptors in DNA repair.

Methods

DNA damage and repair activity were quantified with the use of single-cell gel electrophoresis and plasmid end-joining assays. Cell cycle progression and apoptosis were determined by bromodeoxyuridine and TdT-mediated dUTP nick end labelling assays. Stable transfection was accomplished with the lipofection procedure. Protein interaction and expression were determined by immunoprecipitation and western blotting.

Results

17β-Estradiol (E2) and all-trans retinoic acid (RA) had opposing effects on DNA damage and breast cancer cell survival after double-strand break damage. Treatment with E2, but not with RA, resulted in complex formation between ERα, CBP, and BRCA1 in ER-positive cell lines. Mutant BRCA1 reduced the expression and activity of DNA damage repair proteins but did not block nuclear hormone-dependent effects. Mutant BRCA1 failed to form complexes with ERα and CBP, which correlated with its ability to exert E2-independent effects on DNA repair. Mutant BRCA1 inhibited cell cycle progression and produced increased survival in cells with double-strand breaks. Ectopic ERα expression reproduced the E2-mediated effects on DNA damage, repair, and survival.

Conclusion

The present study proposes a new mechanism by which ER and RAR regulate BRCA1-mediated DNA repair by means of CBP.
Appendix
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Metadata
Title
New role for nuclear hormone receptors and coactivators in regulation of BRCA1-mediated DNA repair in breast cancer cell lines
Authors
David L Crowe
Matt K Lee
Publication date
01-02-2005
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2006
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/bcr1362

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