Claudin-Low Breast Cancer: A Novel Subtype Associated with Basal-Like Phenotype and Metaplastic Breast Cancer.
Shaolei Lu, Kamaljeet Singh, Shamlal Mangray, Rose Tavares, Lelia Noble, Ronald A DeLellis, Murray Resnick, Evgeny Yakirevich. Alpert Medical School of Brown University, Providence, RI
Background: Tight junction proteins are key molecular components governing cellular adhesion, polarity, and glandular differentiation. Loss of tight junction integrity is an important step in tumor progression and metastasis. Gene expression profiling has enabled the stratification of breast cancers into distinct molecular subtypes, such as luminal, HER2+ and basal-like. Recently, a novel claudin-low molecular subtype of breast cancer has been described. Our goal was to investigate the protein expression patterns of claudins in the different molecular subtypes of breast cancer and to better characterize the claudin-low subtype.
Design: On the basis of IHC expression of ER, HER2, CK5/6 and EGFR a total of 253 consecutive grade 3 invasive ductal carcinoma cases were stratified into 73 luminal (ER+), 70 HER2 positive (HER2+), and 97 basal-like, including 18 metaplastic breast carcinomas (ER-, HER2-, CK5/6 and /or EGFR+). Tissue microarrays were analyzed for expression of claudins 1,3,4,7 and 8 by IHC and scored semiquantitatively based on the extent and intensity on a scale of 0-3+.
Results: In the normal breast luminal cells exhibited membranous claudin staining for all of the claudins studied. Low expression (0-1+) was detected in 83% of tumors stained for claudin 1, 68% claudin 3, 59% claudin 4, 56% claudin 7, and 60% claudin 8. Low expression of all five claudins was detected in 36 of 253 cases (14.2%) and this group was designated the claudin-low. The majority of the claudin-low subgroup were basal-like cancers (26 of 36, 72.2%). In contrast, only 4 of 36 (11.1%) tumors were of the luminal phenotype and 6 of 36 cases (16.7%) were HER2+ (P<0.001). Within the basal-like subgroup, 78% of the metaplastic and 15.2% of the non-metaplastic tumors were claudin-low. The claudin-low group was strongly associated with disease recurrence (P=0.006). The most prominent histologic features of the claudin-low subgroup were nested rather than syncytial growth pattern, prominent desmoplasia, central scar, and marked lymphocytic response.
Conclusions: This study is the first to comprehensively examine expression of claudins 1,3,4,7 and 8 in the different molecular subtypes of breast cancer. Molecular subtypes of breast cancer are a heterogeneous group and can be further subdivided into a claudin low group. Claudin-low subtype is a frequent phenomenon in metaplastic and basal-like breast cancer and appears to be a strong predictor of disease recurrence. The loss of claudin expression in basal-like and metaplastic subgroups suggests its role in epithelial-to-mesenchymal transition.
Monday, February 28, 2011 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 38, Monday Morning