Increased CpG methylation of the estrogen receptor gene in BRCA1-linked estrogen receptor-negative breast cancers

Abstract

A distinctive feature of BRCA1-linked breast cancers is that they typically do not express estrogen receptor-a (ERa). Previous investigation suggests that methylation of CpGs within the ERa promoter mediates repression of gene expression in some ERa-negative breast cancers. To determine if methylation of CpGs within the ERa promoter is associated with BRCA1-linked breast cancers, we evaluated methylation in exon 1 of the ERa gene in 40 ERa-negative breast cancers, 20 of which were non BRCA1-linked and 20 BRCA1-linked. CpG methylation was evaluated by either methylationsensitive restriction digest (HpaII), methylation-sensitive PCR (MSP), or direct sequencing of bisulfite-treated genomic DNA. Results from HpaII digests and MSP documented a high degree of methylation, the MSP data showing slightly higher methylation in the BRCA1-linked group. CpGs analysed by direct sequencing showed an overall average methylation of 25% among non BRCA1-linked cancers and 40% among BRCA1-linked cancers (P=0.0031). The most notable difference was found at five particular CpGs, each of which exhibited a greater than twofold increase in methylation in the BRCA1-linked group compared to the non BRCA1-linked group (P50.03 for each CpG). Methylation of certain critical CpGs may represent an important factor in transcriptional repression of the ERa gene in BRCA1-linked breast cancers.

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

“…Many studies, including ours, show that epigenetic inactivation of BRCA1 may also play an important role in a subset of breast tumors. Indeed, many tumors that do not carry BRCA1 mutations have been designated as "BRCA1-like," both by histopathological criteria and by analysis of distinctive genome-wide transcription patterns [29,30]. It is not currently known what triggers the genetic and epigenetic events that result in the "BRCA1-like" phenotype but it is plausible that dysregulation of DNA methylation inactivates multiple susceptible genes simultaneously during tumorigenesis, including BRCA1 and ER.…”

Wilms' Tumor 1 Suppressor Gene Mediates Antiestrogen Resistance via Down-Regulation of Estrogen Receptor-α Expression in Breast Cancer Cells

“…Whereas ER-positive tumors tend to be localized and respond well to hormonal manipulation (26), ER-negative tumors are more aggressive, disseminate widely, and do not respond to hormone therapy (5). A number of mechanisms for the development of ERa negativity have been identified (27)(28)(29)(30)(31)(32). This includes hypermethylation of the ERa promoter in f60% of cases (33) and repression by transcription factors such as pRB2/p130 and LMO4 (34,35).…”

Hypermethylation of CpG Islands in Primary and Metastatic Human Prostate Cancer

“…These 16 CpG islands were chosen because they were each found to be hypermethylated in other human cancers and are known to have many functions in carcinogenesis, including tumor suppression, modulation of inflammation, detoxification, and drug resistance (8,22,(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38). The relatively large sample sizes and number of genes examined, the unique collection of cancer and benign tissues, the tissue processing and purification techniques used in the study design, and the quantitative nature of the assays used in this study are well-suited to accomplishing its goals.…”

“…Comparison of the frequency of methylation at 16 CpG islands in primary prostate cancer and various other primary cancers. A review of the literature was performed to determine the frequencies of methylation in various cancers at the 16 CpG islands examined in the current study (8,22,(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38). These frequencies were then plotted along with the frequencies of methylation determined for primary prostate cancer in the current study.…”