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.
Highlights
In 2007, while conducting comparative gene expression analysis between transgenic mouse models of breast cancer and human breast cancer data sets, Herschkowitz et al discovered a novel molecular subtype of breast cancer which they named ‘claudin-low’ (CL) [1]
Subsequent to this report, a number of groups have further characterized this new tumor subtype and shown that CL tumors account for 7–14% of all invasive breast cancers, are enriched for genes associated with epithelial to mesenchymal transition (EMT), immune cell infiltration, IFNγ activation, mammary stem cells/breast tumor initiating cells and typically demonstrate high levels of genomic instability [2,3,4,5]
As other authors have identified low expression of claudin 7 as being a characteristic feature of CL tumors, we examined the expression of claudin 7 across the breast cancer subtypes in our in silico database
Summary
In 2007, while conducting comparative gene expression analysis between transgenic mouse models of breast cancer and human breast cancer data sets, Herschkowitz et al discovered a novel molecular subtype of breast cancer which they named ‘claudin-low’ (CL) [1]. This subtype was characterized by the low expression of genes involved in tight junctions and epithelial cell-cell adhesion, including claudins 3, 4 and 7, occludin and E-cadherin. They have been associated with a poor prognosis with some evidence that they may be relatively resistant to conventional chemotherapeutic agents [2, 3]
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