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MicroRNA-Mediated Inhibition of Prostate-Derived Ets Factor Messenger RNA Translation Affects Prostate-Derived Ets Factor Regulatory Networks in Human Breast Cancer

Department of Pathology and Laboratory Medicine, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina

Requests for reprints: Dennis K. Watson, Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425. Phone: 843-792-3962; Fax: 843-792-3940; E-mail: watsondk{at}musc.edu.

Key Words: microRNAs • PDEF • transcription factor • ETS • breast cancer

Prostate-derived Ets factor (PDEF) is an ETS transcription factor expressed in normal tissues with high epithelial cell content and noninvasive breast cancer cells. A putative tumor suppressor PDEF protein expression is often lost during progression to a more invasive phenotype. Interestingly, PDEF mRNA has been found to be retained or even overexpressed in the absence of protein; however, the mechanisms for this remain to be elucidated. This study identifies two microRNAs (miRNA) that directly act on and repress PDEF mRNA translation, leading to the loss of PDEF protein expression and the gain of phenotypes associated with invasive cells. In addition, we show that these miRNAs are elevated in human breast tumor samples. Together, these data describe a mechanism of regulation that explains, for the first time, the lack of correlation between PDEF mRNA and protein levels, providing insight into the underexplored role of posttranscriptional regulation and how this contributes to dysregulated protein expression in cancer. These observations have critical implications for therapeutically targeting miRNAs that contribute to cancer progression. [Cancer Res 2008;68(20):8499–506]