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

Disclosures

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.

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.

processing....