P3-03-07: A Novel Approach Integrating microRNA and mRNA Signatures of HMAPK Signaling Is Highly Predictive of ER- Status and Outcome in Breast Cancer – Role of HMAPK microRNAs in Repression of ER and p27.

Abstract

Abstract Deregulation of the MAPK signaling pathway in breast cancer is known to facilitate the down-regulation of the estrogen receptor and to contribute to the aggressive nature of ER negative and triple negative breast cancers. We have identified a microRNA signature indicative of hyperactive MAPK (hMAPK) signaling, which complements a previously established hyperactive MAPK gene expression signature. We have shown that hMAPK signaling also alters the regulatory activity of many microRNAs, including particular microRNAs with established roles in the biology of breast cancer, miR-221/222 and miR-22. Expression correlation with both the hMAPK microRNA signature and hMAPK mRNA signature is significantly associated with ER-negative status, increased tumor grade, high proliferation rate, and, importantly, poor disease specific survival among breast cancer patients, regardless of ER status. The hMAPK microRNA signature contains 127 microRNAs, 47 up-regulated and 70 down-regulated. Of note, hMAPK up-regulated microRNAs include miR-221/222 and 22, both of which have been demonstrated to target ER while miR-221/222 targets the cell cycle regulatory protein p27. Down-regulated microRNAs include miR-375, which positively regulates ER expression by down-regulating expression of an ER repressor. miR-221/222 and miR-22 exhibit both enhanced expression and enhanced regulatory activity in the context of hMAPK signaling, indicating an important role for these microRNAs in the biology of hMAPK signaling in breast cancer. In addition to these microRNAs, an unbiased approach of determining MAPK regulated microRNAs targeting the 3’ UTRs of both ER and p27 will identify novel microRNAs involved in the MAPK regulated repression of ER and p27. These data not only suggest a regulatory role for microRNAs whose expression and biological activity are altered under conditions of hyperactivation of MAPK signaling in establishing and maintaining ER negativity and tumor aggression, but also indicate that hMAPK signaling may represent a novel aggressive tumor biology that is indicative of poor disease outcome in breast cancer. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-03-07.