Evidence supports a critical role for microRNAs in regulation of tissue specific differentiation and development. Signifying a disruption of these programs, miRNA profiling has revealed extensive dysregulation in tumors compared with healthy tissue. The malignant contribution of some miRNAs is understood, however, in other instances the pathways affected by aberrant miRNA expression have yet to be characterized. The miR-200 family has been established as a key regulator of epithelial phenotype and as such, is deeply involved in EMT-like processes in cancer. While exploring a model of transformation of normal mammary epithelium we observed epigenetic silencing of the miR-200 family- as was previously identified in breast cancer cell lines. Here we show the class III histone deacetylase SIRT1 overexpression in a TGF-β driven model of transformation as well as in patient samples of early stage breast cancer. We establish SIRT1 transcript as subject to novel regulation of the miR-200 family, through miR-200a / miR-141 targeting. Moreover, we demonstrate that downregulation of miR-200 family members contributes at least in part to the overexpression of SIRT1, a proposed oncogene in breast cancer. Restoration of miR-200a or knockdown of SIRT1 results in decreased growth in soft agar and decreased invasion. These observations provide further evidence of the important tumor suppressive role of miR-200 family members in breast epithelium, as well as identifying a novel regulatory mechanism that may contribute to SIRT1 upregulation early in breast tumorigenesis.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 107. doi:10.1158/1538-7445.AM2011-107

©2011 American Association for Cancer Research
2011