The role of noncoding transcripts in glucose-dependent gene regulation in estrogen receptor-positive breast cancer

Around seventy percent of breast cancers are of the estrogen receptor-positive (ER+) molecular subtype. Conventional treatments include endocrine therapy that antagonizes ER signaling with tamoxifen or aromatase inhibitors. However, over 50% of patients later develop resistance and relapse. Understanding the underlying molecular mechanisms by which ER drives breast cancer will provide new opportunities to diagnose and therapeutically target it. In this regard, we focused on the part of the genome that is pervasively transcribed to produce noncoding transcripts that are overexpressed in the presence of estrogen. These transcripts are advantageous for tracking disease progression due to their specific expression patterns. We resorted to understanding the function of an intergenic noncoding transcript, “long noncoding RNA 16 ( LNC16 )” that we previously characterized. Since ER can also be activated by specific signaling pathways in the absence of its ligand, investigating the role of LNC16 in an estrogen-independent context could provide insights into the mechanisms underlying the development of resistance and/or the progression toward relapse. Metabolic reprogramming, especially the preference for undergoing glycolysis, is one of the hallmarks of cancer, and affects various signaling pathways, which could also have integral implications in the ligand-independent activation of ER. To study LNC16 's role in glucose-dependent gene expression in ER+ breast cancer in the luminal breast cancer cell line, using CRISPR, LNC16 knockout MCF7 cells (KOs) were created and treated with glucose. We also introduced LNC16 into MCF7 cells using a doxycycline-inducible overexpression system and treated them with glucose. Then we performed genome-wide transcriptomic analyses to identify the genes and pathways regulated. Gene ontology analysis of unique differentially expressed genes (DEGs) under normal glucose conditions showed plausible roles of LNC16 in nucleosome assembly, in regulating cell-cell communication, adhesion, and junction, as well as in signaling pathways. Similarly, unique DEGs in higher glucose conditions predominantly have functions in adhesion, signaling, and chromatin remodeling. We also examined the expression of condition-specific DEGs in breast cancer tumors and identified the association with specific clinical outcomes. Currently, we are elucidating LNC16 's molecular mechanism by which it regulates gene expression to drive ER+ breast cancer biology using cell- and mouse-based experiments. Collectively, these results suggest that estrogen-regulated transcripts can regulate glucose-dependent gene expression to control ER+ breast cancer phenotypic outcomes.