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.
Highlights
Breast cancer remains a prevalent cause of cancer-related death in women worldwide and is categorized into at least five molecular subtypes that differ from each other in terms of biomarkers, etiology, and treatment modalities (Sabatier et al 2014)
We investigate the global response to estrogen stimulation by analyzing paired messenger and miRNA measurements over time in MCF-7 breast cancer cells
Based on these computational predictions, we confirm experimentally that miR-503 suppresses proliferation in MCF-7 cells, and we identify a new target of miR-503, the oncogene ZNF217
Summary
Breast cancer remains a prevalent cause of cancer-related death in women worldwide and is categorized into at least five molecular subtypes that differ from each other in terms of biomarkers, etiology, and treatment modalities (Sabatier et al 2014). The ER, in particular ERα (encoded by the ESR1 gene), has been widely studied in breast cancer (Creighton et al 2006; Oh et al 2006; Zhou and Slingerland 2014). ERα binds to estrogen (usually estradiol or E2), dimerizes, and translocates to the nucleus where it recruits coactivators or corepressors to estrogen response elements (EREs) (Zhou and Slingerland 2014). ERα is thought to be the primary receptor involved in the estrogen response of both normal and breast cancer cells (Higa and Fell 2013). Available online through the RNA Open Access option
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