Basal-like and Triple-negative Breast Cancers

A Critical Review With an Emphasis on The Implications for Pathologists and Oncologists

Sunil Badve; David J Dabbs; Stuart J Schnitt; Frederick L Baehner; Thomas Decker; Vincenzo Eusebi; Stephen B Fox; Shu Ichihara; Jocelyne Jacquemier; Sunil R Lakhani; José Palacios; Emad A Rakha; Andrea L Richardson; Fernando C Schmitt; Puay-Hoon Tan; Gary M Tse; Britta Weigelt; Ian O Ellis; Jorge S Reis-Filho


Mod Pathol. 2011;24(2):157-167. 

In This Article

Relationship Between Basal-like Breast Cancer and BRCA1 Germ-line Mutations

There is increasing evidence to suggest a link between BRCA1 pathway and basal-like breast cancers.[82,83] The majority of tumors arising in BRCA1 germ-line mutation carriers, in particular those diagnosed before 50 years of age, have morphological features similar to those described in basal-like cancers[84,85] and show a basal-like phenotype as defined by immunohistochemistry[86,87] or expression arrays.[8]

Both basal-like breast cancers and tumors arising in BRCA1 germ-line mutation carriers show a peculiar pattern of cell-cycle protein expression;[54,84,88,89] both rarely harbor CCND1 gene amplification;[54,88] however, they express significantly lower levels of p27,[84,89] and higher levels of Skp2,[84,89] cyclin E,[84,89] and caspase-3,[89] when compared with sporadic breast carcinomas and BRCA2 mutation tumors.

Although they lack BRCA1 somatic mutations, sporadic basal-like cancers show similar molecular genetic profiles to tumors arising in BRCA1 mutation carriers.[90–94] 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 >60% 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.[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. In contrast, reconstitution of BRCA1 in ER− BRCA1 mutant cell lines has been shown to lead to upregulation of ER and downregulation of CK5, CK17, and P-cadherin.[99,100] Taken together, BRCA1 dysfunction appears to be one of the drivers of basal-like breast cancers and of a subgroup of triple-negative tumors.


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