Molecular Characteristics and Therapeutic Vulnerabilities of Claudin-low Breast Cancers Derived from Cell Line Models.

Abstract

Breast cancers constitute heterogeneous tumor groups and their categorization in subtypes based on the expression of the estrogen (ER), progesterone (PR) and HER2 receptors has advanced therapeutics. Claudin-low breast cancer has been proposed as an additional subtype which is mostly ER, PR and HER2 negative, but its identification has not led to corresponding specific treatments yet. Breast cancer cell lines from the Cancer Cell Line Encyclopedia (CCLE) were assessed for mRNA suppression of claudins and mRNA expression of ER and ERBB2 (the gene encoding HER2). The set of identified claudin-low cell lines were compared with representative ER-/ERBB2- cell lines for associated molecular alterations, gene dependencies through CRISPR and microRNA arrays and in vitro drug sensitivities using the Genomics of Drug Sensitivity in Cancer (GDSC) project. Claudin-low cell lines display up-regulation of mRNA expression of epithelial to mesenchymal transition (EMT) regulators. Methylation sensitive genes are down-regulated in claudin-low lines compared with other cell lines, without associated up-regulation of DNA methyltransferases. Dependency screen microarrays reveal dependencies of claudin-low cell lines on components of the cytoskeleton but no consistent dependencies in known oncogenes or tumor suppressors. Potential drug sensitivities revealed in the drug screens included sensitivities to WNT pathway modulators, tyrosine kinase cascade inhibitors and BET inhibitors. On the other hand, claudin-low cell lines showed resistance to deacetylase inhibitors. Claudin-low cell line models duplicate features of claudin-low breast cancers and may serve as guides for identification of drugs worth exploring for further development.