Regulation of DNA Damage Response by Estrogen Receptor β-Mediated Inhibition of Breast Cancer Associated Gene 2.

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

doi:10.3390/biomedicines3020182

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 ERβ and negatively regulate the expression and function of the estrogen receptor α (ERα) in MCF-7 breast cancer cells. Upon Erb-041-mediated ERα down-regulation, the transcription of an ERα 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, γH2AX 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.

Highlights

Breast cancer is the most frequently diagnosed site-specific cancer in the female population in the world
We found that h incubation with Erb-041 decreased chromatin-bound estrogen receptor α (ERα) (Figure 1B, lane 2 vs. lane 1)
These results indicate that Erb-041 reduces ERα chromatin association and breast cancer-associated gene 2 (BCA2) transcription

Summary

Introduction

Breast cancer is the most frequently diagnosed site-specific cancer in the female population in the world. By blocking estrogen receptors (ER), the proliferation and metastatic potential of early stage breast cancers can be inhibited by aromatase inhibitors and selective ER modulators, such as Arimidex, Aromasin, Tamoxifen and Faslodex [1]. The reduced production of estrogen as well as competitive drug binding with ERα (estrogen receptor α) prevents ER−estrogen complexes from forming and translocating to the nuclei to trigger the transcription of growth-promoting genes. As ERα transactivates genes that promote accelerated DNA synthesis and cell proliferation, high levels of estrogens increase DNA damage and the risk of breast and ovarian cancer. Estrogen promotes the transcription of BRCA1 via binding with an ERα/p300 complex, and facilitates DNA double-stranded break (DSB)

Results

Discussion

Conclusion