Abstract
BackgroundMicroRNAs (miRNAs) are small, non-coding, endogenous RNAs involved in regulating gene expression and protein translation. miRNA expression profiling of human breast cancers has identified miRNAs related to the clinical diversity of the disease and potentially provides novel diagnostic and prognostic tools for breast cancer therapy. In order to further understand the associations between oncogenic drivers and miRNA expression in sub-types of breast cancer, we performed miRNA expression profiling on mammary tumors from eight well-characterized genetically engineered mouse (GEM) models of human breast cancer, including MMTV-H-Ras, -Her2/neu, -c-Myc, -PymT, -Wnt1 and C3(1)/SV40 T/t-antigen transgenic mice, BRCA1fl/fl;p53+/-;MMTV-cre knock-out mice and the p53fl/fl;MMTV-cre transplant model.ResultsmiRNA expression patterns classified mouse mammary tumors according to luminal or basal tumor subtypes. Many miRNAs found in luminal tumors are expressed during normal mammary development. miR-135b, miR-505 and miR-155 are expressed in both basal human and mouse mammary tumors and many basal-associated miRNAs have not been previously characterized. miRNAs associated with the initiating oncogenic event driving tumorigenesis were also identified. miR-10b, -148a, -150, -199a and -486 were only expressed in normal mammary epithelium and not tumors, suggesting that they may have tumor suppressor activities. Integrated miRNA and mRNA gene expression analyses greatly improved the identification of miRNA targets from potential targets identified in silico.ConclusionsThis is the first large-scale miRNA gene expression study across a variety of relevant GEM models of human breast cancer demonstrating that miRNA expression is highly associated with mammary tumor lineage, differentiation and oncogenic pathways.
Highlights
MicroRNAs are small, non-coding, endogenous RNAs involved in regulating gene expression and protein translation. miRNA expression profiling of human breast cancers has identified miRNAs related to the clinical diversity of the disease and potentially provides novel diagnostic and prognostic tools for breast cancer therapy
Since the p53fl/fl ;mammary tumor virus (MMTV)-cre and BRCA1fl/fl;p53+/-; MMTV-cre tumors were derived from mice with different strain backgrounds compared to the other models in the FVB/N background (Table 1), we initially determined whether significant differences in miRNA were associated with the various background strains
Hierarchical clustering of the expression of these miRNAs across all of the mouse mammary tumor models indicated that the expression levels of the 22 miRNAs in the tumors were not related to the background strain of the mouse (Additional file 2)
Summary
MicroRNAs (miRNAs) are small, non-coding, endogenous RNAs involved in regulating gene expression and protein translation. miRNA expression profiling of human breast cancers has identified miRNAs related to the clinical diversity of the disease and potentially provides novel diagnostic and prognostic tools for breast cancer therapy. MicroRNAs (miRNAs) are small, non-coding, endogenous RNAs involved in regulating gene expression and protein translation. MiRNA expression profiling of human breast cancers has identified miRNAs related to the clinical diversity of the disease and potentially provides novel diagnostic and prognostic tools for breast cancer therapy. Altered expression of miRNAs has been associated with many human diseases, including cancer [4,5]. In addition to mRNA gene expression profiling, miRNA expression analyses of human breast cancers have further demonstrated another layer of the molecular diversity of this disease and may potentially be a useful diagnostic and prognostic tool for breast cancer therapy and treatment. A group of miRNAs, including miR-221/222, miR-206, miR-18a, and miR-22, have been reported to be involved in the regulation of ERa at either the transcriptional or posttranscriptional level [10,11], thereby presenting attractive targets for therapeutic intervention in ERa-negative breast cancer. Patients with tumors of a basal, hormone receptor- and Her2-negative phenotype generally have a poorer prognosis than patients whose tumors express hormone receptors and are responsive to hormone therapy
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