Abstract 1598: LncRNA AK001796 as a therapeutic target in aggressive breast cancers

Abstract

Abstract Breast cancer is a heterogeneous disease that can be classified into several distinct molecular subtypes based on gene expression. Like mRNAs and miRNAs, long noncoding RNAs (lncRNAs) differ dramatically in expression across subtypes and can be used for classification. While there has been considerable emphasis on miRNAs, our knowledge is still lacking about the role of lncRNAs that comprise the majority of the mammalian transcriptome. Recently, the importance of lncRNAs in cancer has been highlighted by several studies. We have examined the expression profiles of >17,000 lncRNAs in a large set of breast tumors and have identified a lncRNA, AK001796, that is overexpressed in aggressive breast cancers. In particular, AK001796 is enriched in the aggressive claudin-low, HER-enriched, and luminal B subtypes. Furthermore, in four different models, we find that AK001796 is significantly upregulated in cell lines induced to undergo EMT and in putative mesenchymal-like cancer stem cells within cell lines suggesting this lncRNA as an inducer/facilitator of EMT. Similar results were obtained when a lung cancer cell line was induced to EMT through TGF beta treatment. Using cell fractionation, we have discovered that AK001796 is maintained predominantly in the nucleus. By RACE we have identified two isoforms of AK001796 in breast cancer cells that differ by the presence or absence of a 94 nucleotide intron. The short form (with intron spliced out) appears to be the variant enriched following EMT and may serve as a marker of aggressiveness. Interestingly, knockdown of AK001796 using antisense oligonucleotides lead to significantly increased apoptosis in EMT positive cell lines whereas in EMT negative cells knockdown had little effect. Preliminary studies for finding out the protein interacting partners identified some mesenchymal phenotype-associated proteins in pull-down studies using biotinylated oligos. To further investigate the molecular mechanisms regulated by AK001796 and its utility as a therapeutic target, we will determine the pathways induced by AK001796 by mapping its protein interaction network and downstream signaling pathways. These results nominate AK001796 as a promising therapeutic target in aggressive breast cancers. Citation Format: Maneesh Kumar, Rebecca Sinnott DeVaux, Julia J. Shen, Steven P. Davis, Marcel E. Dinger, John S. Mattick, Charles M. Perou, Jeffrey M. Rosen, Sendurai A. Mani, Jason I. Herschkowitz. LncRNA AK001796 as a therapeutic target in aggressive breast cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1598.