Claudin-Low Breast Cancer; Clinical & Pathological Characteristics

Abstract

Claudin-low breast cancer is a molecular type of breast cancer originally identified by gene expression profiling and reportedly associated with poor survival. Claudin-low tumors have been recognised to preferentially display a triple-negative phenotype, however only a minority of triple-negative breast cancers are claudin-low. We sought to identify an immunohistochemical profile for claudin-low tumors that could facilitate their identification in formalin fixed paraffin embedded tumor material. First, an in silico collection of ~1600 human breast cancer expression profiles was assembled and all claudin-low tumors identified. Second, genes differentially expressed between claudin-low tumors and all other molecular subtypes of breast cancer were identified. Third, a number of these top differentially expressed genes were tested using immunohistochemistry for expression in a diverse panel of breast cancer cell lines to determine their specificity for claudin-low tumors. Finally, the immunohistochemical panel found to be most characteristic of claudin-low tumors was examined in a cohort of 942 formalin fixed paraffin embedded human breast cancers with >10 years clinical follow-up to evaluate the clinico-pathologic and survival characteristics of this tumor subtype. Using this approach we determined that claudin-low breast cancer is typically negative for ER, PR, HER2, claudin 3, claudin 4, claudin 7 and E-cadherin. Claudin-low tumors identified with this immunohistochemical panel, were associated with young age of onset, higher tumor grade, larger tumor size, extensive lymphocytic infiltrate and a circumscribed tumor margin. Patients with claudin-low tumors had a worse overall survival when compared to patients with luminal A type breast cancer. Interestingly, claudin-low tumors were associated with a low local recurrence rate following breast conserving therapy. In conclusion, a limited panel of antibodies can facilitate the identification of claudin-low tumors. Furthermore, claudin-low tumors identified in this manner display similar clinical, pathologic and survival characteristics to claudin-low tumors identified from fresh frozen tumor material using gene expression profiling.

Re-definition of claudin-low as a breast cancer phenotype

“…The claudin-low breast cancer subtype was discovered seven years later in an integrated analysis of human and murine mammary tumors (3). The existence of this subtype has later been observed in several independent breast cancer cohorts (4)(5)(6)(7)(8)(9), and an analogous claudin-low subtype has been identified in bladder cancer (10,11).…”

“…The claudin-low breast cancer subtype is defined by gene expression characteristics, most prominently: Low expression of cell-cell adhesion genes, high expression of epithelialmesenchymal transition (EMT) genes, and stem cell-like/less differentiated gene expression patterns (12). Beyond these gene expression features, claudin-low tumors have marked immune and stromal cell infiltration (9,12), but are in many other aspects remarkably heterogeneous. No specific genomic aberrations accurately delineate claudin-low tumors, and there is a greater variation in mutational burden and degree of copy number aberration (CNA) than in the other breast cancer subtypes (13).…”

High-level cytoplasmic claudin 3 expression is an independent predictor of poor survival in triple-negative breast cancer

“…In a recent paper [21] the claudin-low subtype, defined as TNBC with low-level IHC expression two of four proteins (i.e. E-cadherin, and claudins 3, 4 and 7), was associated with exceedingly good RFS, with a local recurrence rate of only 1.3% at 10-year follow-up.…”

“…Claudins are tight junctional proteins of [20][21][22][23][24] kDa that are present on the apicolateral membranes of epithelial, endothelial and mesothelial cells [1,2]. They have barrier and fence functions, and they take part in signal transduction [2].…”

“…TNBCs are enriched in basal-like (BLBC) and claudin-low breast cancer molecular subtypes, the former expressing basal cell markers and the latter, in addition to low claudin 3, 4, 7 and E-cadherin expression, showing induced expression of EMT (epithelialto-mesenchymal transition)-related genes, immune systemrelated genes and stem-cell features [18,19]. The estimated incidence of claudin-low breast cancer is 7-14% and longterm prognosis is relatively poor [19][20][21].…”