Abstract 3946: Investigation of a hyperactive MAPK microRNA expression profile reveals potential role for microRNAs in the generation and maintenance of ER- phenotype in breast cancer
Authors: Philip C. Miller, Jennifer Clarke, Tulay Koru-Sengal, Joeli Brinkman, Dorraya El-Ashry
Journal: Cancer Research (2011)

Abstract microRNAs (miRNAs) are small RNAs around 22 nucleotides in length that function as important regulators of cell and tissue specific gene regulation, and have been shown to have critical functions in development and differentiation. Dysregulation of miRNA biogenesis and biological activity has emerged as a facet of normal biology that is usurped by cancers to promote aberrant growth and tumorigenesis. miRNA expression has been shown to discriminate among various types of cancer; for example, miRNA expression profiling correctly classifies canonical breast cancer subtypes. We have previously demonstrated that many breast cancers have enhanced signaling through the ErbB family, resulting in a gene expression signature driven by hyperactive MAPK (hMAPK) signaling that is indicative of ER status, and correlates with poor clinical outcome in breast cancer gene expression datasets. We have shown that inhibiting hMAPK signaling in a subset of ER- breast cancers results in re-expression of ER and re-establishment of anti-estrogen sensitivity. Our model system is ideally suited to study the contribution of miRNAs to the generation and maintenance of the ER- phenotype established by hMAPK signaling in breast cancer. In this study, we generated a hMAPK miRNA signature, at both the miRNA expression and miRNA activity levels. These miRNA expression and activity profiles correlate well with the hMAPK regulated mRNAs in our model of hMAPK signaling. Importantly, several of these hMAPK regulated miRNAs are known to control expression of key genes involved in the biology of ER- breast cancer, such as ER, p27KIP1, and known tumor suppressors. Pathway analysis of these miRNAs reveals potential regulation of many important biological pathways; indeed, several of these miRNAs have established roles in regulating numerous biological pathways which are often dysregulated in breast cancer. We examined the representation of this miRNA expression signature in clinical breast cancer specimens, as well as in primary cultures derived from dissociated ER- breast tumors, and investigated the correlation of this signature with various clinical features. The hMAPK miRNA profile correlates with grade, ER status, and clinical outcome. These data suggest that MAPK regulation of key miRNAs, and thus key biological pathways, is involved in establishing and maintaining phenotypes associated with hMAPK signaling in breast cancer. While mRNA and miRNA expression data independently are proven tools for tumor diagnosis and prognosis, combined analysis of gene expression and miRNA expression will provide a more powerful means for investigating and understanding the complexities of tumor biology. Here we have used such an approach to further understand and appreciate the involvement of hyperactivation of MAPK signaling pathways in the biology of ER- breast cancer. 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 3946. doi:10.1158/1538-7445.AM2011-3946