EMT Features in Claudin-Low versus Claudin-Non-Suppressed Breast Cancers and the Role of Epigenetic Modifications

Background: Breast cancers are heterogeneous and are classified according to the expression of ER, PR and HER2 receptors to distinct groups with prognostic and therapeutic implications. Within the triple-negative group, with no expression of these three receptors, molecular heterogeneity exists but is currently not exploited in the clinic. The claudin-low phenotype is present in a subset of triple-negative breast cancers and constitutes together with basal-like cancers the most extensive groups within triple-negative breast cancers. Suppression of epithelial cell adhesion molecules in claudin-low cancers is also a hallmark of Epithelial Mesenchymal Transition (EMT). Methods: The groups of claudin-low and claudin-non-suppressed breast cancers from the extensive publicly available genomic cohorts of the METABRIC study were examined to delineate and compare their molecular landscape. Genetic and epigenetic alterations of key factors involved in EMT and potentially associated with the pathogenesis of the claudin-low phenotype were analyzed in the two groups. Results: Claudin-low cancers displayed up-regulation of several core transcription factors of EMT at the mRNA level, compared with claudin-non-suppressed breast cancers. Global promoter DNA methylation was increased in both groups of triple-negative cancers and in claudin-low ER-positive cancers compared with the rest of ER-positive cancers. Histone modifier enzymes, including methyltransferases, demethylases, acetyltransferases and deacetylases displayed amplifications more frequently in claudin-non-suppressed triple-negative cancers than in claudin-low counterparts and the expression of some of these enzymes differed significantly between the two groups. Conclusion: Claudin-low and claudin-non-suppressed triple-negative breast cancers differ in their landscape of EMT core regulators and epigenetic regulators. These differences may be explored as targets for therapeutic interventions specific to the two groups of triple-negative breast cancers.