No evidence for breast cancer susceptibility associated with variants of BRD7, a component of p53 and BRCA1 pathways

Abstract

BRD7 (bromodomain 7), a subunit of poly-bromo-associated BRG1-associated factor (PBAF)-specific Swi/Snf chromatin remodeling complexes, has been proposed as a tumour suppressor protein following its identification as an important component of both functional p53 and BRCA1 (breast cancer 1, early onset) pathways. As low BRD7 expression levels have been linked to p53-wild-type breast tumour cells, we hypothesized an implication of BRD7 germline alterations in the pathogenesis of hereditary breast cancer similar to that of TP53 in Li-Fraumeni syndrome. We performed sequence analysis of the BRD7 gene on 61 high-risk individuals with hereditary or very-early-onset breast cancer and 100 healthy controls. Four potentially disease-causing single-nucleotide alterations were detected within the cohort of breast cancer patients (one listed as a rare single-nucleotide polymorphism (SNP) in the NCBI (National Center for Biotechnology Information) SNP database). Two of the detected variants were also each found once within the control collective. Segregation analysis on both families of those carrying the remaining two variants revealed segregation of these BRD7 alterations independent of breast cancer. In conclusion, it seems that the BRD7 variants we detected represent rare polymorphisms and mainly rule out BRD7 as a frequent high-penetrance breast cancer susceptibility gene. However, further analyses in larger cohorts of women with hereditary breast cancer should clarify the role of BRD7 in breast cancer predisposition.

Integrating ChIP-sequencing and digital gene expression profiling to identify BRD7 downstream genes and construct their regulating network

“…BRD7 regulates signaling pathways that involve cell growth, apoptosis, cell cycle, and mobility [14][15][16][17][18][19][20][21]. As a component of SWI/SNF chromatin-remodeling complexes, BRD7 interacts with other transcriptional factors, such as BRD2 [15], BRCA1 [22], and p53 [16], and transcriptionally regulates their target genes and downstream signaling pathways.…”

“…BRD7 can inhibit cell growth through multiple mechanisms, including cell cycle arrest and apoptosis [14,15]. Recent work suggests that BRD7 acts as a transcriptional cofactor binding to BRCA-1 and p53 and is essential for the transcriptional activation of p53 target genes such as p21, MDM2, and TIGAR [16][17][18]. BRD7 is also a subunit of the SWI/SNF complex specific for polybromo BRG1-associated factor (PBAF) [19], modulates chromatin Electronic supplementary material The online version of this article (doi:10.1007/s11010-015-2568-y) contains supplementary material, which is available to authorized users.…”

Design and synthesis of potent and selective inhibitors of BRD7 and BRD9 bromodomains

“…12 However, it was found that BRD7 mutations represent rare polymorphisms in breast cancer, with no pathogenic effect. 17 MicroRNA-200c (miR-200c), which is over-expressed in endometrial carcinoma, inhibits BRD7 expression. 18 With little known about the molecular function of BRD7, and even less in the case of BRD9, potent and selective small molecule inhibitors would be valuable tools to study the roles of these proteins in transcription, elucidate their roles in oncology and other human diseases, and to test them as drug targets.…”

Expression and subcellular localization of the bromodomain-containing protein 7 is a prognostic biomarker in breast cancer

“…In breast cancer, BRD7 was downregulated and even deleted on chromosome 16q12, in p53-wild-type but not mutant breast cancer cells [12]. Other studies proved that BRD7 was not a frequent high-penetrance susceptibility gene in breast cancer because its variants represented only rare polymorphisms [21] and no pathogenic BRD7 germ-line mutations were found in Triple Negative Breast Cancer patients with familial bC, ruling out the role of BRD7 in the genetic predisposition to breast cancer [22].…”