BRCA1 dysfunction in sporadic basal-like breast cancer

被引:436
作者
Turner, N. C.
Reis-Filho, J. S.
Russell, A. M.
Springall, R. J.
Ryder, K.
Steele, D.
Savage, K.
Gillett, C. E.
Schmitt, F. C.
Ashworth, A.
Tutt, A. N.
机构
[1] Breakthrought Breast Canc Res Ctr, Chester Beatty Labs, Inst Canc Res, London SW3 6JB, England
[2] Univ Porto, Inst Mol Pathol & Immunol, IPATIMUP, P-4100 Oporto, Portugal
[3] Univ Porto, Fac Med, P-4100 Oporto, Portugal
[4] Breast Pathol Lab, London, England
关键词
BRCA1; basal-like; breast cancer; ID4; metaplastic;
D O I
10.1038/sj.onc.1210014
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Basal-like breast cancers forma 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 = 0.72), BRCA1 messenger RNA expression was twofold lower in basal-like breast cancers compared to matched controls (P = 0.008). ID4, a negative regulator of BRCA1, was expressed at 9.1-fold higher levels in basal-like breast cancer (P < 0.0001), 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 (P < 0.0001). 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.
引用
收藏
页码:2126 / 2132
页数:7
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