BRCA1 dysfunction in sporadic basal-like breast cancer

Abstract

Basal-like breast cancers form a distinct subtype of breast cancer characterized by the expression of markers expressed in normal basal/myoepithelial cells. Breast cancers arising in carriers of germline BRCA1 mutations are predominately of basal-like type, suggesting that BRCA1 dysfunction may play a role in the pathogenesis of sporadic basal-like cancers. We analysed 37 sporadic breast cancers expressing the basal marker cytokeratin 5/6, and age-and grade-matched controls, for downregulation of BRCA1. Although BRCA1 promoter methylation was no more common in basal-like cancers (basal 14% vs controls 11%, P ¼ 0.72), BRCA1 messenger RNA expression was twofold lower in basal-like breast cancers compared to matched controls (P ¼ 0.008). ID4, a negative regulator of BRCA1, was expressed at 9.1-fold higher levels in basal-like breast cancer (Po0.0001), suggesting a potential mechanism of BRCA1 downregulation. BRCA1 downregulation correlated with the presence of multiple basal markers, revealing heterogeneity in the basal-like phenotype. Finally, we found that 63% of metaplastic breast cancers, a rare type of basal-like cancers, had BRCA1 methylation, in comparison to 12% of controls (Po0.0001). The high prevalence of BRCA1 dysfunction identified in this study could be exploited in the development of novel approaches to targeted treatment of basal-like breast cancer.

Basal-like and triple-negative breast cancers: a critical review with an emphasis on the implications for pathologists and oncologists

“…Histologically, the majority of basal-like breast cancers is of IDC-NST type, high histological grade, and characterized by exceptionally high mitotic indices, the presence of central necrotic or fibrotic zones, pushing borders, conspicuous lymphocytic infiltrate, and typical/atypical medullary features ( Figure 1). 18,21,32 The similarity of these features with those of human papilloma virus-induced squamous cell carcinoma of the head and neck has led to the identification of the role of retinoblastoma gene (RB1) in these tumors. 33 However, not all basal-like cancers are of the IDC-NST type; the majority of medullary and atypical medullary, 4,34-36 metaplastic, 4,37,38 secretory, 39 myoepithelial, and adenoid cystic carcinomas 4,40 of the breast also show a basal-like phenotype.…”

“…[90][91][92][93][94] This may be in part due to the presence of a dysfunctional BRCA1 pathway in these tumors. 32,82,83 BRCA1 gene promoter is methylated in 460% of medullary 95,96 and metaplastic 32 breast cancers of basal-like phenotype. Sporadic invasive ductal carcinomas with basal-like phenotype express ID4, a negative regulator of BRCA1, 97,98 at significantly higher levels than grade-matched controls.…”

“…Sporadic invasive ductal carcinomas with basal-like phenotype express ID4, a negative regulator of BRCA1, 97,98 at significantly higher levels than grade-matched controls. 32 This mechanism may account for the low levels of BRCA1 expression in sporadic basal-like carcinomas of ductal morphology. Importantly, recent studies have demonstrated that BRCA1 gene silencing leads to downregulation of ER 99 and upregulation of genes considered to be markers of basal-like cancers, 100 including CK5, CK17, and P-cadherin.…”

“…129 Finally, as mentioned earlier, a group of basal-like and triple-negative breast carcinomas have been shown to have a dysfunctional BRCA1 pathway. 32,65,[81][82][83] A significant number of these cases lack competent homologous recombination DNA repair. This subgroup may be amenable to specific therapeutic strategies such as inhibitors of the PARP enzyme.…”

MTA1-mediated transcriptional repression of BRCA1 tumor suppressor gene

“…Mutations in BRCA1 account for about 10-15% of familial breast cancers; however, the role of BRCA1 in sporadic breast cancer has been ambiguous. Although hyper-methylation and loss of heterozygosity on chromosome 17 has been associated with sporadic breast cancer, very little is known about BRCA1's transcriptional repression (Turner et al, 2007). Recent data suggest that the Ets-2 transcription factor may play a role in the repression of the BRCA1 promoter (Baker et al, 2003).…”