Differential Claudin 3 and EGFR Expression Predicts BRCA1 Mutation in Triple-Negative Breast Cancer

Abstract

BRCA-1 mutation-associated triple-negative breast cancer (TNBC) has been hypothesized to exhibit a phenotype that is distinct from non-mutation carriers. We have analyzed immunohistochemically detected cytokeratins 5 and 14, epidermal growth factor receptor (EGFR), claudin (CLDN) 3, 4, and 7, and E-cadherin in 57 TNBC (32 BRCA1 and 8 BRCA2 tumors, 17 WT tumors). Positive staining of CLDN3 and negative EGFR expression in TNBC are associated with a BRCA1 mutation. EGFR and CLDN3 expression was able to predict the presence of BRCA1 mutation (area under curve 0.802, p < 0.001). This could help in guiding the decision for BRCA testing.

Incorporating immunohistochemical markers into screening methods for BRCA1-mutated breast cancer

“…The multivariate regression model by Danzinger et al (2018) revealed that claudin-3 was 22 times more likely to be observed in BRCA1-mutated triple negative breast cancer (TNBC) in comparison to BRCA2 and non-mutated TNBC. What is more, expression of claudin-3 was an independent marker of BRCA1 mutation status in TNBC in a univariate analysis [55]. Van Heerma Voss et al (2014) described overexpression of claudin-3, -6 and -7 in BRCA1-mutated tumor tissue in comparison to adjacent healthy tissue.…”

“…Mavaddat et al (2010) also highlighted a potentially important role of ER, CK5/6 and CK14 in prediction of BRCA1-mutated cases [96]. On the other hand, Danzinger et al (2018) found no significant correlation between expression levels of CK5 and CK14 among the BRCA1, BRCA2 and non-mutated group in TNBC. In the performed ROC analysis they found that claudin-3 and EGFR expression levels were able to predict BRCA1 mutation status in TNBC with fairly high sensitivity and specificity (area under curve 0.802, p < 0.001) [55].…”

“…Although many analyses have been conducted, there is no consensus about its utility in prediction of the BRCA1 mutation in BC. Danziger et al (2018) found that the lack of expression of EGFR in tumor tissue was associated with BRCA1 mutation status when compared to wild-type TNBC despite common expression of this protein in basal-like BC [55], the most common phenotype in BRCA1-related breast tumors [77,78,79]. In contrast, Collins et al (2009) found no statistically significant difference in EGFR expression between BRCA1 mutation carriers and negative cases of TNBC [80].…”

Role of Claudin Proteins in Regulating Cancer Stem Cells and Chemoresistance-Potential Implication in Disease Prognosis and Therapy

“…Claudin-7 expression correlated with shorter overall survival in gastric cancer patients, while the overall survival was increased in patients with claudin-18 expression. Recently, claudin-3 and -7 are also considered as novel prognostic factors in triple-negative breast cancer (TNBC) through its aberrant immunohistochemical expressions [107]. Claudin-3 cytoplasmic expression is an indicator of poor survival in triple-negative breast cancer.…”

“…In an interesting article by Danzinger et al, the importance of claudin-3 in triple-negative breast cancer (TNBC) was documented. It was reported that claudin-3 expression was correlated with a Breast cancer type 1 (BRCA1) mutation [107]. This could help in guiding the decision for BRCA testing for triple-negative breast cancer (TNBC).…”