Objective: Recent genome-wide studies revealed that as much as 80% of the human genome can be transcribed whereas only 2% of this RNA is translated into proteins. Non-coding transcripts can be subdivided into several groups, with long non-coding RNAs (lncRNAs) representing the largest and most diverse class. With breast cancer being the most frequent malignancy in women worldwide, we set out to investigate the potential of lncRNAs as novel therapeutic targets.

Methods: We focused on the luminal B and the HER2/neu-positive subtypes of breast cancer, as both are associated with high prevalence and bad prognosis. By performing RNA-Seq on tumor sections and mammary organoids from MMTV-PyMT and MMTV-Neu-NDL mice, modeling the luminal B and HER2/neu-amplified subtypes of human breast cancer respectively, we generated a comprehensive catalog of differentially expressed lncRNAs. We functionally validated the role of a subset of these lncRNAs by antisense oligonucleotide (ASO) mediated knockdown in primary mammary tumor cells and 3D ex vivo organoids.

Results: We identified several hundred potentially oncogenic lncRNAs that were over-expressed in a subtype-specific manner as well as numerous lncRNAs up-regulated in both MMTV-PyMT and MMTV-Neu-NDL tumors. To narrow down the candidate list of lncRNAs with the highest therapeutic potential, we sorted the data computationally and defined a subset of previously uncharacterized lncRNAs as Mammary Tumor Associated RNAs (MaTARs). Upon independent knockdown of several MaTARs, we observed significantly reduced cell proliferation, invasion and/or collective cell migration in a cancer-specific context.

Conclusion: MaTARs are likely important drivers of mammary tumor progression and/or metastasis and represent promising new therapeutic targets. Future studies will focus on the molecular characterization of these lncRNAs and elucidation of their potential role(s) in mammary tumor progression and metastasis.

Citation Format: Sarah D. Diermeier, Kung-Chi Chang, Susan M. Freier, Frank Rigo, C. Frank Bennett, David L. Spector. Long noncoding RNAs as targets of mammary tumor cell proliferation and migration. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr A43.