BRCA1 as a tumor suppressor linked to the regulation of epigenetic states: keeping oncomiRs under control

BRCA1 is a tumor suppressor gene known to be implicated in the development of a subset of breast and ovarian cancers. The tumor suppressor properties of BRCA1 are generally thought to be linked to the gene's critical roles in the network of DNA damage response. In a recent report, BRCA1-mediated epigenetic repression at the promoter region of miRNA-155 was identified as a novel mechanism by which BRCA1 carries out its tumor suppressor functions.


Background
Inherited mutations in BRCA1 greatly increase the risk of breast cancer [1]. Tumors arising in mutation carriers have generally lost the wild-type BRCA1 allele [2]. Th ese fi ndings have led to the defi nition of BRCA1 as a tumor suppressor. Th e BRCA1 gene has well-established roles in maintenance of genomic integrity, including DNA repair by homologous recombination, DNA decatenation, and regulation of centrosomes [3]. In accordance, extensive changes in chromosome structure and number are observed in tumors derived from carriers [4,5]. Th e tumor suppressor functions of BRCA1 are therefore commonly attributed to its role in genomic maintenance. Th e BRCA1 gene has other roles, however, including those related to cellular diff erentiation and transcriptional regulation. miRNAs are small noncoding RNAs (~22 nucleotides) that mediate post-transcriptional gene silencing by control ling the translation of mRNA into protein products [6]. In cancer, miRNAs are diff erentially expressed when compared with the corresponding normal tissue, and some have tumor suppressor properties whereas others are oncogenic (so-called oncomiRs) [7,8]. In a recent report, Chang and colleagues identifi ed a novel role for BRCA1 as an important mediator of epigenetic repression of an oncomiR; that is, miRNA-155 [9].

The article
Change and colleagues report substantial diff erences in the ability of R1669Q, a BRCA1 mutation currently of unknown clinical signifi cance (single amino-acid substitution), to rescue lethality of Brca1-null ES cells compared with wild-type BRCA1 [9]. Th e functional assays carried out suggest a signifi cant role for the R1699Q mutation in tumor suppression. Nevertheless, R1699Qexpressing embryonic stem cells (Brca1 null) were not sensitive to DNA-damaging agents and did not show genomic instability. Th is fi nding is interesting, given the critical role carried out by BRCA1 gene products in the cellular response to DNA damage.
Using microarrays, high expression of miRNA-155 was found in R1699Q cells and was validated in further experiments. Th e BRCA1 binding site was identifi ed, and validated, at the promoter region of miRNA-155. Th e authors then show that BRCA1 mediates chromatin remodeling at the promoter region of miRNA-155 through direct protein-protein interactions with histone deace tylase 2 [9]. Th is was established by experiments involving targeted muta tion of promoter binding sites, chromatin immuno precipitations and inhibition of histone deacetylases. Th e experiments that followed suggested oncogenic proper ties in association with miRNA-155, based on ectopic expression in cell lines injected into mice and data in human breast cancer samples showing high miRNA-155 in association with BRCA1 defects.

The viewpoint
In studying the eff ects of BRCA1 R1699Q, a mutation of unknown clinical signifi cance, Chang and colleagues discovered a novel mechanism for BRCA1 as a tumor suppressor gene [9]. Th is mechanism involves the binding of BRCA1 gene products to the promoter region of Abstract BRCA1 is a tumor suppressor gene known to be implicated in the development of a subset of breast and ovarian cancers. The tumor suppressor properties of BRCA1 are generally thought to be linked to the gene's critical roles in the network of DNA damage response. In a recent report, BRCA1-mediated epigenetic repression at the promoter region of miRNA-155 was identifi ed as a novel mechanism by which BRCA1 carries out its tumor suppressor functions. miRNA-155 (a known oncomiR), where they mediate epigenetic repression through protein-protein interactions with histone deacetylase 2. Interestingly, what emerges from this study is that R1699Q products retain DNA repair activities. In this regard, examining the phenotype of breast cancers aris ing in R1699Q carriers will be of considerable interest. Together with the analysis of sporadic cancers, with respect to miRNA-155 and basal or stem cell/progenitor markers, this could lead to a better understanding of the develop ment of basallike breast cancers. Clearly, this analysis will involve experimentally validating the targets of miRNA-155, and determining whether there are other genes regulated by this same mechanism -that is, BRCA1-mediated epigenetic repression.
Th e clinical implications that arise from this research relate to recent progress made in clinical trials showing promising anti-cancer eff ects from inhibitors of poly-ADP-ribose poly merase (PARP) in treatment of patients with inherited mutations in BRCA1 or BRCA2 [10]. Th e eff ectiveness of PARP inhibitors in this regard relates to loss of the wild-type allele in cancer cells of mutation carriers, resulting in defective DNA repair by homologous recombination [11]. PARP inhibitors will thus probably not be eff ective in treatment of patients with the R1699Q mutation. In sporadic cases of breast cancer, however, the BRCA1 gene is inactivated by epigenetic mechanisms [12,13] rather than by acquired point mutations [14]. We have previously reported that a substantial fraction of sporadic breast cancers have acquired CpG island hypermethy lation of the BRCA1 gene and that their evolutionary path is similar to breast cancers arising in BRCA1 mutation carriers [4,12,13,15]. Most importantly, BRCA1 hypermethylation predicts response to PARP inhibitors at the same level as BRCA1 germline mutations [16]. In this regard, the question arises of whether miRNA-155 can be used as a biomarker to guide treatment selection with respect to PARP inhibitors or DNA-damaging agents. Further, there have been considerable eff orts in determining whether circulating miRNAs in blood can be used as biomarkers for early detection of cancer [7] -based on its potential early involvement, miRNA-155 could represent a candidate marker in this respect.