Estrogen receptor α, BRCA1, and FANCF promoter methylation occur in distinct subsets of sporadic breast cancers

Abstract

Estrogen receptor α (ER) and its ligand estrogen play vital roles in the development, progression and treatment of breast cancer. An increasing number of studies have also provided evidence linking disruption of the Fanconi anemia/BRCA cascade to breast cancer. Our objectives were to examine the methylation status and expression profiles of ER, correlate the findings with BRCA1 and FANCF methylation and map the critical CpGs for ER expression. We found that the CpG islands in the 5′ region of the ER gene are methylated in 59 of 120 (49.2%) primary breast cancers, including 45 of 59 ER-negative tumors (76.3%, P < 0.00001). In addition, we observed a strong correlation between ER promoter and BRCA1 promoter methylation (odds ratio 3.12, 95% confidence interval 1.10-9.68, P = 0.02). In contrast, FANCF methylation was rare in breast tumors: one of 120 (0.8%). ER methylation was associated with high tumor grade (60.4% methylated vs. 39.6% unmethylated in grade 3 tumors, P = 0.04) and tumor subtype (P = 0.03). Though small in number, all tumors of the medullary subtype were ER methylated. In contrast, the lobular subtype had the least methylation (23.1% methylated vs. 76.9% unmethylated). After treatment of MDA-MB-231 cells with 5-aza-cytidine (5-aza-dC) and trichostatin, which resulted in re-expression of ER mRNA, we localized dramatic demethylation effects to CpG islands in positions +68, +165, +192, +195, +337, +341 and +405 from transcription start site of the ER promoter. These data suggest that unlike FANCF, both ER and BRCA1 are specifically targeted for methylation in sporadic breast cancers, a phenomenon that should be explored for development of novel diagnostic and therapeutic approaches. HHS Public Access

CpG Island Methylation Profile of Estrogen Receptor Alpha in Iranian Females with Triple Negative or Non-triple Negative Breast Cancer: New Marker of Poor Prognosis

“…They also found that methylation in tumor with higher grade is significantly higher than that in lower grade tumors. Meanwhile, a significant correlation between the hormone receptors and methylation status was also reported (Wei et al, 2008) With regard to the methylation status of ER3, 41.7% of the samples were methylated in our study, and no significant correlation was found between ER3 methylation status and prognostic factors, such as tumor size and grade, lymph node involvement, and IHC markers, including ER, PgR, HER-2, and p53. Higher methylation rate of ER3 in the right breast of premenopausal patients was prominently significant.…”

“…A survey of the literature shows that the reported frequency of CpG island methylation in the promoter region of ER-α in Chinese (Zhao et al, 2008), Turkish (Buyru et al 2009), North American and Korean (Lee et al, 2008), American (Wei et al, 2008), and Indian (Mirza et al, 2007) women with breast cancer is different, and a diverse impact on the prognosis of cancer has also been reported in different countries. The frequency of methylation in different ER in the current study is not exactly similar to the previously reported studies, but considerable similarities of methylation frequency of each ER, i.e.…”

“…Furthermore, aberrant promoter methylation of cancerrelated genes, such as ER-α in sporadic breast tumors and their nonrandom distributions has also been investigated (Parrella et al, 2004). The different frequencies of ER-α gene silencing via promoter hypermethylation have been reported in Chinese (Zhao et al, 2008), Turkish (Buyru et al, 2009), North American and Korean (Lee et al, 2008), American (Wei et al, 2008), and Indian (Mirza et al, 2007) women with breast cancer, thus revealing the diverse impact on the prognosis of cancer. As far as the methylation status of ER-α has not been mapped in triple negative tumors and its impact has not been compared with non-triple negative tumors, current study was sought to evaluate the hypermethylation pattern of CpGs across the ER gene CpG island in Iranian females with triple negative and non-triple negative breast tumors and impact of methylation profile in the clinicopathological features.…”

SIRT1 Deacetylates the DNA Methyltransferase 1 (DNMT1) Protein and Alters Its Activities

“…As an example, DNMT1 recruits HDAC1 to the estrogen receptor ␣ (ESR1) promoter to turn off expression of ESR1 in MDA-MB-231 breast cancer cells (50,75). Cotreatment of cells with TSA and the methyltransferase inhibitor 5-aza-dC reactivates transcription of ESR1 (22,71). In addition, it has been reported that SIRT1 associates with the Ecadherin (CDH1) promoter, which can also be silenced in MDA-MB-231 cells (27,56).…”

Time to Think Outside the (Genetic) Box

“…Ongoing work is attempting to identify "phenocopies" of BRCA1-associated breast cancers in hopes of distinguishing tumors with intact BRCA1 genes but therapeutic vulnerabilities [e.g., to poly(ADP-ribose) polymerase-1 (PARP1) inhibitors] similar to those of tumors with mutated BRCA1. The potential role of BRCA1 methylation in non-BRCA1 (mutation)-associated breast carcinomas has been difficult to clearly characterize, despite the identification of methylated BRCA1 in larger subsets of basal-like and familial non-BRCA1 (mutation)-associated than in hereditary BRCA1 breast tumor cells (8,9). Defining the characteristics of BRCA1-associated tumors has been challenging (10); perhaps, the novel classification system used by Wong et al will help to shed light on this confusion and permit a clearer focus on the role of epigenetic mechanisms.…”