Molecular profiling of human breast cancers has defined 5 molecular subtypes: luminal A, luminal B, HER2 over-expressing, basal-like and claudin-low. The claudin-low subtype was identified in 2007 and is characterized by low expression of claudin proteins, E-cadherin and markers of luminal differentiation, and is reported to be associated with expression of mesenchymal and cancer stem cell (CSC) markers. The prevalence of this subtype is reported to be between 7-14% and there are an excess of tumors with metaplastic and medullary-like features, an association with poor prognosis and evidence that they may be resistant to conventional chemotherapies. Using information from publicly available gene expression microarray data, we sought to identify immunohistochemical markers of the claudin-low subtype and to further describe the morphological features of claudin-low breast tumors and the overall survival characteristics of patients with these tumors, along with any associations between these tumors and CSC markers.
Using the gene expression microarray datasets, we performed hierarchical clustering to assign a molecular subtype to the tumors. Differential gene expression analysis was used to identify genes that were significantly upregulated and downregulated between claudin-low tumors and other tumor subtypes as candidates for immunohistochemical markers for our formalin fixed paraffin embedded (FFPE) tumor cohort. We utilized 943 stage I or stage II, lymph node negative primary invasive breast cancers treated with breast conserving surgery and adjuvant radiation, which had FFPE tumor blocks available for tissue microarray construction. On the basis of IHC expression of ER, PR, HER2, Ki67, EGFR, CK5/6, Claudin proteins and E-cadherin, tumors were classified as luminal A, luminal B, HER2 over-expressing, basal-like or claudin-low. Kaplan-Meier methods were used to estimate overall survival, and Fisher's exact tests were used to compare tumor characteristics and expression of CSC markers (ALDH1, CD44hi/CD24low) between claudin-low and luminal A tumors. Claudin-low tumors comprised 8% of our cohort with an overall survival of 73.6% at a median follow up of 12 years, similar to that of basal-like and HER2 over-expressing subtypes. Compared to luminal A type tumors, the claudin-low tumors were statistically more likely to have circumscribed tumor margins. However, there was no statistically significant association between claudin-low subtype and the expression of CSC markers. The claudin-low subtype represents a minority of invasive breast cancers, however this group is characterized by poor prognosis, and as such the identification of these tumors is useful to determine treatment options in the clinical setting.
Citation Format: Kay Dias, Anna Dvorkin-Gheva, Greg Pond, Mark Levine, Timothy Whelan, Anita Bane. Characterization of claudin-low breast cancers. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr A124.