Promoter methylation status and expression of estrogen receptor alpha in familial breast cancer patients

Abstract

The hypermethylation of estrogen receptor alpha (ERα) promoter is a common molecular alteration in sporadic breast cancer (BC), but its involvement in familial BC remains largely unknown. In the present study, we analyzed the methylation statuses of four regions (ER1, ER3, ER4, and ER5) of the ERα promoter and the ERα expression levels of 113 familial BC patients in a Han Chinese Population from northeastern China and evaluated the association between major clinicopathological features and the hypermethylation statuses of the ERα gene. Tumor samples were analyzed for ERα methylation status by the methylation-specific polymerase chain reaction for ERα, PR, p53, BRCA-1, and BRCA-2 by immunohistochemical (IHC) staining and for Her-2 status by IHC and fluorescence in situ hybridization (FISH). ERα methylation was observed in tumor tissues in 47/113 (41.6%) familial BC patients. There were no significant differences in the methylation statuses among ER1 (20.4%), ER3 (18.6%), ER4 (17.7%), and ER5 (19.5%; χ (2) = 3.89, p > 0.05). An association between ERα expression level and its promoter methylation level was found. In addition, ERα methylation was significantly correlated with tumor size, PR expression, p53 nuclear accumulation, and BRCA-1 and BRCA-2 statuses. In conclusion, in familial BC patients, the level of ERα gene promoter methylation correlates with ERα expression, PR, p53 nuclear accumulation, and BRCA-1 and BRCA-2 statuses. Epigenetic alteration of ERα gene may play an important role in the pathogenesis of familial BC.

Expression of DNA methyltransferases in the mouse uterus during early pregnancy and susceptibility to dietary folate deficiency

“…nuclear hormone receptors, are influenced by DNA methylation in the endometrium, myometrium, ovary, and breast (Piva et al 1989, Lapidus et al 1996, Hori et al 2000, Ghabreau et al 2004, Mehrotra et al 2004, Ren et al 2007, Suzuki et al 2008, Li et al 2010, Wei et al 2012. These finding further suggest that the levels of DNMTs in endometrial tissues are regulated by estrogen and progesterone during menstruation.…”

Estrogen and its role in thyroid cancer

“…Epigenetic pathways regulate gene transcription by DNA methylation and post-translational modification of histones. DNA methylation may silence the promoter of the ESR1 gene that encodes ERa, which occurs in the pathogenesis of different cancers (Yao et al 2010, Wei et al 2012. In breast cancer, DNA hypermethylation is a major reason for the loss of ERa expression and confers a poor prognosis to this tumor (Ramos et al 2010).…”

Epigenetic regulation of estrogen signaling in breast cancer

“…Some studies also suggest that DNA methylation-mediated promoter ESR1 (estrogen receptor 1 gene) silencing is found frequently and may participate in tumorigenesis or progression of the disease in other cancers, such as leukemia or colon tumors 14 . The etiology of the loss of expression of ERα (about 30% of BC patients are ERα - ) is due to DNA hypermethylation in 41% of cases, which correlates with tumor size and histological grade 15 - 17 . Moreover, a recent study on BC patients in India revealed that the proportion of ESR1 hypermethylation was highly increased in triple negative tumors 18 .…”