Regulation of DNA damage response by estrogen receptor β-mediated inhibition of breast cancer associated gene 2

Yuan Hao Lee, Youping Sun, Leo E. Gerweck, Randolph D. Glickman

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Accumulating evidence suggests that ubiquitin E3 ligases are involved in cancer development as their mutations correlate with genomic instability and genetic susceptibility to cancer. Despite significant findings of cancer-driving mutations in the BRCA1 gene, estrogen receptor (ER)-positive breast cancers progress upon treatment with DNA damaging-cytotoxic therapies. In order to understand the underlying mechanism by which ER-positive breast cancer cells develop resistance to DNA damaging agents, we employed an estrogen receptor agonist, Erb-041, to increase the activity of ERß and negatively regulate the expression and function of the estrogen receptor a (ERa) in MCF-7 breast cancer cells. Upon Erb-041-mediated ERa down-regulation, the transcription of an ERa downstream effector, BCA2 (Breast Cancer Associated gene 2), correspondingly decreased. The ubiquitination of chromatin-bound BCA2 was induced by ultraviolet C (UVC) irradiation but suppressed by Erb-041 pretreatment, resulting in a blunted DNA damage response. Upon BCA2 silencing, DNA double-stranded breaks increased with Rad51 up-regulation and ataxia telangiectasia mutated (ATM) activation. Mechanistically, UV-induced BCA2 ubiquitination and chromatin binding were found to promote DNA damage response and repair via the interaction of BCA2 with ATM, ?H2AX and Rad51. Taken together, this study suggests that Erb-041 potentiates BCA2 dissociation from chromatin and co-localization with Rad51, resulting in inhibition of homologous recombination repair.

Original languageEnglish (US)
Pages (from-to)182-200
Number of pages19
JournalBiomedicines
Volume3
Issue number2
DOIs
StatePublished - Jun 1 2015

Keywords

  • BCA2
  • DNA damage response
  • Erb-041
  • Rad51
  • UVC

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)

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