Triple negative breast cancers (TN, negative for hormone receptors and HER2), which include basal and non-basal subtypes, are of interest because they resemble cancers of BRCAl mutation carriers and are frequent in young women and African-American women. Although PARP1 inhibitors, targeting defective DNA damage responses, are promising treatments for TN cancers, additional therapeutic targets for these aggressive cancers are needed. Defining the microRNA (mlR) expression profiles of TN cancers will allow identification of altered signal pathways and specific target proteins that may lead to development of rationally targeted therapies. Because individual miRs control expression of multiple proteins and their signal pathways, and give simple expression profiles that can stratify subclasses of specific tumor types, it is likely that mlR expression profiles will identify subclasses of the TN subtype, and signal pathways that could serve as therapeutic targets for specific subclasses. We propose to define the signal pathways driving important biological features of TN breast cancers by profiling miR expression signatures of TN cancers and associated premalignant lesions. The miR expression signatures will be used to define signal pathways regulated by miRs that are significantly up and down-modulated in TN cancers and precursor lesions. Signaling networks that control the biology of TN basal and non-basal breast cancers will be defined through 4 specific aims: 1) preparation of 365 case TN breast cancer tissue microarray (TMA) and cores for RNA preparation;2) definition of basal and non-basal miR profiles, confirmation of cell type expression of miRs by in situ hybridization (ISH) and association of specific miRs with biochemical and clinical features;3) preparation of a 256 case TN breast cancer and premalignant lesion TMA;RNA isolation from 100 basal cancers and associated premalignant lesions after laser capture microdissection (LCM) and definition of mlR profiles;4) definition of targets of miRs characteristic of TN cancer subclasses and premalignant lesions, confirmation of targets and their signal pathways, using breast cancer-derived cell lines;manipulation of the miR signal networks to determine biological effects in breast cancer cell lines;Identify therapeutic targets.
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