BRCA1 methylation: a significant role in tumour development?

Catteau, Aurélie; Morris, Joanna R.

doi:10.1016/s1044-579x(02)00056-1

Cited by 104 publications

(68 citation statements)

References 84 publications

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“…When analysing primary tumour samples of patients with secondary AML, we found BRCA1 hypermethylation only in breast cancer samples. The number of samples analysed is small, but three of four breast cancers showed BRCA1 hypermethylation, which might indicate that in breast cancer complicated by a t-AML, the frequency of BRCA1 hypermethylation is higher than the 11 -31% reported in the literature (Catteau and Morris, 2002). As patients treated for breast cancer are at particular risk for t-AML, it will be of interest to study whether BRCA1 hypermethylation can identify the patients at increased risk for this complication.…”

Section: Discussionmentioning

confidence: 89%

“…Mutations of BRCA1 occur in at least 10% of inherited breast cancers, but are very rare in sporadic breast cancer. BRCA1 expression is repressed through promoter hypermethylation in 11 -31% of breast, 5 -15% of ovarian cancer and about 60% of pancreatic ductal carcinoma (Catteau and Morris, 2002;Peng et al, 2006). The biologic effects of the loss of BRCA1 gene function caused by promoter hypermethylation and by coding-region mutations in breast and ovarian cancer produce similar microarray patterns of reduced gene expression (Hedenfalk et al, 2001).…”

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confidence: 99%

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Reduced BRCA1 expression due to promoter hypermethylation in therapy-related acute myeloid leukaemia

et al. 2006

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BRCA1 plays a pivotal role in the repair of DNA damage, especially following chemotherapy and ionising radiation. We were interested in the regulation of BRCA1 expression in acute myeloid leukaemia (AML), in particular in therapy-related forms (t-AML). Using real-time PCR and Western blot, we found that BRCA1 mRNA was expressed at barely detectable levels by normal peripheral blood granulocytes, monocytes and lymphocytes, whereas control BM-mononuclear cells and selected CD34 þ progenitor cells displayed significantly higher BRCA1 expression (P ¼ 0.0003). Acute myeloid leukaemia samples showed heterogeneous BRCA1 mRNA levels, which were lower than those of normal bone marrows (P ¼ 0.0001). We found a high frequency of hypermethylation of the BRCA1 promoter region in AML (51/133 samples, 38%), in particular in patients with karyotypic aberrations (P ¼ 0.026), and in t-AML, as compared to de novo AML (76 vs 31%, P ¼ 0.0002). Examining eight primary tumour samples from hypermethylated t-AML patients, BRCA1 was hypermethylated in three of four breast cancer samples, whereas it was unmethylated in the other four tumours. BRCA1 hypermethylation correlated to reduced BRCA1 mRNA (P ¼ 0.0004), and to increased DNA methyltransferase DNMT3A (P ¼ 0.003) expression. Our data show that reduced BRCA1 expression owing to promoter hypermethylation is frequent in t-AML and that this could contribute to secondary leukaemogenesis.

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Section: Discussionmentioning

confidence: 89%

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confidence: 99%

Reduced BRCA1 expression due to promoter hypermethylation in therapy-related acute myeloid leukaemia

et al. 2006

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“…Methylation of the BRCA1 promoter has previously been linked to reduced mRNA expression in primary breast cancer samples, with proportions ranging from 11 to 31% [6]. It has been reported that BRCA1-associated breast cancers, which predominantly occur in premenopausal women, are more frequently of the ER-negative phenotype [7].…”

Section: Introductionmentioning

confidence: 99%

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

Dignam

Nanda

et al. 2007

Breast Cancer Res Treat

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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

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“…Epigenetic changes in the BRCA1 gene in the form of promoter hypermetylation and loss of expression were reported in a subset of sporadic tumors (7). Only one of many reports describes methylation of the BRCA2 gene (8).…”

Section: Introductionmentioning

confidence: 99%

BRCA1 at the crossroad of multiple cellular pathways: approaches for therapeutic interventions

Yarden

Papa

2006

Molecular Cancer Therapeutics

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Approximately 10% of the cases of breast cancer and invasive ovarian cancer are hereditary, occurring predominantly in women with germ-line mutations in the BRCA1 or BRCA2 genes. Low expression of these genes in sporadic tumors extends their significance to sporadic breast and ovarian cancers as well. For over a decade since its identification, extensive research has been directed toward understanding the function of the breast and ovarian tumor suppressor gene BRCA1. The long-term goal has been to identify the biochemical pathways reliant on BRCA1 that can be exploited for developing targeted therapies and benefit mutation carriers. To date, no one specific role has been identified, but rather it is clear that BRCA1 has significant roles in multiple fundamental cellular processes, including control of gene expression, chromatin remodeling, DNA repair, cell cycle checkpoint control, and ubiquitination, and overall is important for maintenance of genomic stability. Major findings and potential BRCA1-dependent therapies will be discussed.

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BRCA1 methylation: a significant role in tumour development?

Cited by 104 publications

References 84 publications

Reduced BRCA1 expression due to promoter hypermethylation in therapy-related acute myeloid leukaemia

Reduced BRCA1 expression due to promoter hypermethylation in therapy-related acute myeloid leukaemia

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

BRCA1 at the crossroad of multiple cellular pathways: approaches for therapeutic interventions

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