• 2018-07
  • 2018-10
  • 2018-11
  • Our finding that low BRCA expression was not associated


    Our finding that low BRCA1 order Rocilinostat was not associated with basal-like subtype or worse survival is consistent with the lack of evidence that somatic loss of BRCA1 contributes meaningfully to sporadic breast cancer. Only homozygous, not heterozygous, Brca1 knockout mice develop breast cancers (Evers and Jonkers, 2006), whereas breast (and other) cancers develop in Becn1 heterozygous knockout mice (Qu et al., 2003; Yue et al., 2003; Cicchini et al., 2014). Moreover, loss of BRCA1 heterozygosity in humans with germline BRCA1 mutations is necessary for the development of BRCA1 mutant-associated breast cancers (Futreal et al., 1994). This is likely because haploinsufficient BRCA1 expression is sufficient for full DNA repair (Latimer et al., 2005). Thus, given the rare frequency of somatic BRCA1 mutations (despite the high prevalence of BRCA1 order Rocilinostat heterozygous loss) (Futreal et al., 1994), a role for BRCA1 deficiency in sporadic breast cancer is not established. Nonetheless, previous studies have shown similarities between the clinical and molecular features of sporadic basal-like tumors and familial BRCA1-mutated tumors, resulting in the model that basal-like tumors may be associated with BRCA1 dysfunction (Turner et al., 2004, 2007; Valentin et al., 2012; Turner and Reis-Filho, 2006). Low BRCA1 expression and/or BRCA1 promoter methylation has been associated with basal-like sporadic breast cancers in some reports (Turner et al., 2007; Joosse et al., 2011; Lee et al., 2010; Rakha et al., 2008b), but not others (Matros et al., 2005; Richardson et al., 2006). Regardless of their findings, these studies generally analyzed small numbers of patients; did not identify tumor subtypes by molecular profiling; and identified low BRCA1 samples using immunohistochemical staining for protein expression or quantitative PCR for mRNA expression, which are both subject to difficulties in standardization and reproducibility. Our study is the first to apply current state-of-the-art methods for BRCA1 mRNA quantification to a large number of samples characterized by intrinsic molecular subtypes. Our inability to find a relation between BRCA1 expression and basal-like breast cancers supports the concept that the phenotypic similarities of sporadic basal-like breast tumors and hereditary BRCA1 mutated tumors may be explained by factors other than BRCA1 dysfunction (Matros et al., 2005). Alternatively, our data (Fig. 1D) suggests that low BRCA1 expression may characterize only a small subgroup of basal-like tumors, whose specific features are yet to be defined. Another possible explanation is that other factors, besides somatic mutations or decreased mRNA expression (either as a result of copy number variation or epigenetic regulation), act to impair BRCA1 function in sporadic breast cancer. Thus, although our results consistently show a lack of relationship between decreased BRCA1 expression and basal-like breast cancer, they cannot definitively exclude a role for BRCA1 dysfunction in sporadic basal-like breast cancer. We propose that the decreased expression of BECN1 (another tumor suppressor gene located near BRCA1) in sporadic basal-like breast tumors may partly explain the phenotypic overlap of this disease with hereditary BRCA1 breast cancer. Patients with germline mutations in BRCA1 usually have somatic deletion of wild-type chromosome 17q21 in their breast tumors; (Turner et al., 2004; Palacios et al., 2008) thus, the co-deletion of BECN1 in such cases may contribute to the development of basal-like features. Independently of whether the co-deletion of BECN1 plays a role in hereditary BRCA1 breast cancer, decreased BECN1 expression — which results in reduced levels of autophagy (Qu et al., 2003) — may exert effects on the DNA damage repair pathway in sporadic breast cancer similar to those produced by a BRCA1 mutation and loss of heterozygosity in hereditary breast cancer. In support of this theory, knockdown of another essential autophagy gene, ATG5, suppresses the expression of RAD51, a key protein that functions in homologous recombination and repair of DNA double-stranded breaks (Mo et al., 2014).