Abstract A039: The role of long noncoding RNAs in epithelial to mesenchymal transition and cancer stem cells

Abstract

Abstract The claudin-low subtype is generally triple (ER, PR, HER2) negative and there are currently no targeted agents directed at them. These tumors express low levels of tight and adherens junction genes including claudin 3 and E-cadherin, and high levels of markers associated with epithelial-mesenchymal transition (EMT) including Snail, Twist, and Zeb1/2. Claudin-low tumors are also enriched in signatures derived from human tumor-initiating cells and a sorted population enriched for human mammary stem cells. miRNAs are differentially expressed in claudin-low tumors including low expression of the miR-200 family - regulators of EMT and stemness. MiR-200 overexpression in claudin-low cell lines causes them to lose this classification and to adopt an expression profile of another subtype. While there has been considerable emphasis on miRNAs, our knowledge is still lacking about the role of long noncoding RNAs (lncRNAs) that comprise the majority of the mammalian transcriptome. Here, we have examined the expression profiles of >17,000 lncRNAs in a large set of breast tumors. Like mRNAs and miRNAs, lncRNAs differ dramatically in expression across subtypes and can be used for classification. LncRNAs that are differentially regulated in cell lines induced to undergo EMT are associated with claudin-low tumors and we have identified some of these lncRNAs as potential regulators of the EMT/CSC phenotype. We have begun to study the subcellular localization and potential function of a couple of these candidate lncRNAs using RNA FISH and siRNA knockdown respectively. These results suggest major roles for noncoding RNAs in claudin-low breast tumors and in the regulation of breast cancer stem cells. Citation Format: Jason I. Herschkowitz, Cristian Coarfa, Aleix Prat, Michael J. Toneff, Katherine A. Hoadley, Marcel E. Dinger, John S. Mattick, Sendurai A. Mani, Charles M. Perou, Jeffrey M. Rosen. The role of long noncoding RNAs in epithelial to mesenchymal transition and cancer stem cells. [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 A039.