Abstract
Introduction/background: Recent studies have shown that long noncoding RNAs (lncRNAs) could be potential biomarkers and therapeutic targets in cancer. LncRNAs are significant in regulating transcriptional, post-transcriptional, and epigenetic changes in human development. Previously, we identified ~1900 lncRNAs in breast cancer (BC) using advanced technologies including Global Run-On sequencing (GRO-seq) and subcellular fractionation RNA sequencing (RNAseq); intriguingly, many were transcribed bidirectionally, now referred to as divergent lncRNAs. Currently, little is known about their role in regulating estrogen-dependent signaling in BC. In this study, we have investigated the role of a previously annotated and characterized estrogen-regulated lncRNA known as lncRNA67. Materials and Methods: We used integrated genomics to compute expression across BC molecular subtypes. Single-molecule RNA-FISH (Fluorescence in Situ Hybridization) determined its localization in BC patient samples. The role of lncRNA67 in estrogen receptor-positive (ER+) BC cells was investigated using stably inducible lncRNA overexpressing MCF7 and T47D cell lines. Total-directional RNA-seq was performed to understand its effect on global gene expression profiles. Results: LncRNA67 showed distinct expression patterns across molecular subtypes of BC. RNA-FISH revealed nucleus and cytoplasm localization, indicating one to two copies of mature RNA are present in ER+ BC patient cells. Functional assays with reduced expression showed inhibited growth of BC cells. When lncRNA67 was overexpressed in ER+ BC cells, the result correlates with clinical outcome. Gene Set Enrichment Analysis (GSEA) showed its role in regulating estrogen-dependent transcription. Conclusion: Our molecular analyses suggest lncRNA67 plays a pivotal role in ER-dependent and -independent pathways. Taken together, our results indicate that lncRNAs are an integral component of cancer biology. Acknowledgments: S.S.G. is supported by a First-time Faculty Recruitment Award from the Cancer Prevention and Research Institute of Texas (CPRIT; RR170020). S.S.G. is also supported by a grant from Lizanell and Colbert Coldwell foundation.
Citation Format: Enrique I. Ramos, Laura A. Sanchez-Michael, Melina J. Sedano, Barbara Yang, Ramesh Choudhari, Alana L. Harrison, Shrikanth S Gadad. Functional characterization of estrogen-regulated divergent long noncoding RNAs in estrogen receptor-positive breast cancer [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-144.
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