An integrative transcriptomics approach identifies miR-503 as a candidate master regulator of the estrogen response in MCF-7 breast cancer cells

作者：Baran Gale Jeanette; Purvis Jeremy E^*; Sethupathy Praveen^*

来源：RNA-A Publication of the RNA Society, 2016, 22(10): 1592-1603.

DOI：10.1261/rna.056895.116

• estrogen receptor alpha (ER alpha)
• gene expression dynamics
• microRNAs
• miR-503
• breast cancer
• ZNF217

Estrogen receptor alpha (ER alpha) is an important biomarker of breast cancer severity and a common therapeutic target. In response to estrogen, ER alpha 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.

• 出版日期2016-10