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Integrated miRNA and mRNA expression profiling of mouse mammary tumor models identifies miRNA signatures associated with mammary tumor lineage

Min Zhu1, Ming Yi2, Chang Hee Kim3, Chuxia Deng4, Yi Li5, Daniel Medina6, Robert M Stephens2 and Jeffrey E Green1*

Author Affiliations

1 Transgenic Oncogenesis and Genomics Section, Laboratory of Cell Biology and Genetics, Center for Cancer Research, National Cancer Institute, Building 37, Room 4054, 37 Convent Dr., Bethesda, MD 20892, USA

2 Advanced Biomedical Computing Center, NCI-FCRDC, Building 430, Room 127, 1050 Boyles Street, Frederick, MD 21702, USA

3 Laboratory of Molecular Technology, NCI-FCRDC, 915 Toll House Ave, Frederick, MD 21702, USA

4 Mammalian Genetics Section, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, 10 Center Dr., Bethesda, MD 20892, USA

5 Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA

6 Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA

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Genome Biology 2011, 12:R77  doi:10.1186/gb-2011-12-8-r77

Published: 16 August 2011

Abstract

Background

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. 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.

Results

miRNA 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.

Conclusions

This 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.