title: An integrative transcriptomics approach identifies miR-503 as a candidate master regulator of the estrogen response in MCF-7 breast cancer cells.
abstract: Estrogen receptor α (ERα) is an important biomarker of breast cancer severity and a common therapeutic target. In response to estrogen, ERα stimulates a dynamic transcriptional program including both coding and noncoding RNAs. We generate a fine-scale map of expression dynamics by performing a temporal profiling of both messenger RNAs (mRNAs) and microRNAs (miRNAs) in MCF-7 cells (an ER+ model cell line for breast cancer) in response to estrogen stimulation. We identified three primary expression trends-transient, induced, and repressed-that were each enriched for genes with distinct cellular functions. Integrative analysis of mRNA and miRNA temporal expression profiles identified miR-503 as the strongest candidate master regulator of the estrogen response, in part through suppression of ZNF217-an oncogene that is frequently amplified in cancer. We confirmed experimentally that miR-503 directly targets ZNF217 and that overexpression of miR-503 suppresses MCF-7 cell proliferation. Moreover, the levels of ZNF217 and miR-503 are associated with opposite outcomes in breast cancer patient cohorts, with high expression of ZNF217 associated with poor survival and high expression of miR-503 associated with improved survival. Overall, these data indicate that miR-503 acts as a potent estrogen-induced candidate tumor suppressor miRNA that opposes cellular proliferation and has promise as a novel therapeutic for breast cancer. More generally, our work provides a systems-level framework for identifying functional interactions that shape the temporal dynamics of gene expression.
authors.affiliation: Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Jeanette
authors.identifier: 0000-0002-8779-328X
authors.initials: J
authors.lastname: Baran-Gale
authors.affiliation: Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Jeremy E
authors.initials: JE
authors.lastname: Purvis
authors.affiliation: Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Praveen
authors.identifier: 0000-0002-7983-239X
authors.initials: P
authors.lastname: Sethupathy
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects; D004967:Estrogens / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome
chemical_list: D004967:Estrogens; C545473:MIRN503 microRNA, human; D035683:MicroRNAs; D015534:Trans-Activators; C113698:ZNF217 protein, human
keywords: ZNF217; breast cancer; estrogen receptor α (ERα); gene expression dynamics; miR-503; microRNAs