Claudin Expression in High Grade Invasive Ductal Carcinoma of the Breast: Correlation with the Molecular Subtype

Claudin proteins are a major component of the tight junctions. Dysregulation of claudin protein expression has been described in a number of malignancies. Gene expression profiling has stratified breast cancers into distinct molecular subtypes: luminal, HER2+ and basal-like. Recently, a novel claudin-low molecular subtype has been described. In this study we correlated the expression patterns of claudins with the molecular subtypes of breast cancer. On the basis of immunohistochemical expression 226 grade 3 invasive ductal carcinomas were stratified into 65 luminal (ER+), 65 HER2 positive (HER2+), 86 basal-like, including 14 metaplastic carcinomas (ER−, HER2−, CK5/6 and /or EGFR+), and 10 unclassified. Tissue microarrays were analyzed for expression of claudins 1, 3, 4, 7 and 8 by immunohistochemistry and scored semiquantitatively. High levels of expression were detected in 17% of all cases for claudin 1, 32% claudin 3, 41% claudin 4, 44% claudin 7, and 40% claudin 8. Luminal cancers exhibited increased claudins 7 and 8; basal-like tumors demonstrated increased claudins 1 and 4 expression. Low expression of all five claudins was detected in 30 of 226 cases (13%) and this group was designated “claudin-low”. The majority of the claudin-low subgroup were basal-like cancers (23 of 30, 77%). In contrast, only 1 of 30 (3%) claudin-low tumors were of the luminal phenotype and 6 of 30 cases (20%) were HER2+ (P<0.001). Within the basal-like subgroup, 64% of the metaplastic and 19% of the non-metaplastic tumors were claudin-low. The claudin-low group was strongly associated with disease recurrence (P=0.0093). In conclusion, this study is the first to comprehensively examine the differential expression of claudins 1, 3, 4, 7 and 8 in the molecular subtypes of high grade breast cancer. Claudin-low subtype is a frequent phenomenon in metaplastic and basal-like breast cancer and appears to be a strong predictor of disease recurrence.