Cross Species Identification and Functional Analysis of MicroRNAs in Mammary Tumorigenesis: Potential Targets for Detection, Diagnosis and Therapy.

摘要

miRNAs have recently been identified as epigenetic elements that have important roles in development, differentiation, apoptosis and oncogenesis. Altered expression of several miRNAs have been reported in human breast cancers and may be useful in predicting patient prognosis. The functional roles of miRNAs in tumor development and progression have not been well evaluated. The purpose of this study is to use multiple genetically engineered mouse models of mammary cancer as a filter to identify miRNAs whose expression may be evolutionarily conserved in breast cancer. Such species of miRNA that are identified through a cross-species comparison are likely to be functionally important. This study has determined the miRNA expression in multiple mouse models of mammary cancer that are based upon different initiating oncogenic events. Four general patterns of miRNA expression have been identified among the models by hierarchical clustering analyses. A distinct miRNA expression pattern has been identified for MMTV-her2/neu tumors, another for MMTV-myc tumors, whereas p53-/- tumors cluster separately from C3(1)/Tag and MMTV-PyMT tumors. Current analyses are underway to correlate changes in miRNA expression with array CGH and gene expression data from the same tumors and compare these findings to miRNA alterations in human cancer. Functional analyses are also being performed.