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

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 OPEN ACCESSBiomedicines 2015, 3 183 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.

Prolonged use of finasteride-induced gonadal sex steroids alterations, DNA damage and menstrual bleeding in women

“…Some studies showed complex changes of cellular and molecular mechanisms participating in the DNA damage, which are mediated by a diversity of abnormal regulation of aromatase [10,22,[26][27][28]. Also, some other studies considered SAA gene as stress protein marker for DNA damage and cancer, which also support our findings on the DNA damage [10,[28][29][30].…”

“…Some studies showed complex changes of cellular and molecular mechanisms participating in the DNA damage, which are mediated by a diversity of abnormal regulation of aromatase [10,22,[26][27][28]. Also, some other studies considered SAA gene as stress protein marker for DNA damage and cancer, which also support our findings on the DNA damage [10,[28][29][30]. Furthermore, Alkahtane et al [31] were recently found that finasteride administration to female mice has adverse effects within both the short and the long periods in female mice associated with apoptosis induction.…”

The role of estrogen receptor beta in breast cancer

“…This downregulation of ERα occurs through ERβ-Sp1 proteinprotein interactions within the ERα promoter region and recruitment of a corepressor complex containing the nuclear receptor corepressor NCoR, hypoacetylation of histone H4 and displacement of RNA-polymerase II [77]. The use of an ERβ-specific agonist significantly decreases the expression and functional activity of ERα in MCF-7 breast cancer cells, accompanied by decreased transcription of a downstream effector, breast cancerassociated gene 2 (BCA2) [78]. Additional evidence shows that tumors with a low ERα/ERβ ratio have increased oxidative damage, antioxidant enzyme protein levels and uncoupling protein (UCP) and sirtuin 3 (SIRT3) protein levels.…”

The Role of BCA2 in the Endocytic Trafficking of EGFR and Significance as a Prognostic Biomarker in Cancer

“…Further functional links between BCA2 expression and breast cancer pathology have since been explored by other in vitro experiments, clinical expression analyses and genomic studies. The principal findings from these studies indicate that BCA2: 1) is transcriptionally regulated by the ER, 2) can modulate the anti-breast cancer effect of the AMPK inhibitor metformin, 3) can promote proliferation of ER + breast cancer by down-regulating p21, 4) has a role in regulating the DNA damage response, 5) is a potential susceptibility gene for breast cancer and 6) may serve as a potential drug target in anti-breast cancer therapy 18-24.…”