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 positive (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 (
estrogen receptor positive (ER+)), 65 HER2+, 86 basal-like, including 14 metaplastic
carcinomas (ER-, HER2-, CK5/6, and/or
epidermal growth factor receptor positive), and 10 unclassified. Tissue microarrays were analyzed for the 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 expression of
claudins 1 and 4. 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 was 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 examine comprehensively 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.