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Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors

Jason I Herschkowitz12, Karl Simin3, Victor J Weigman4, Igor Mikaelian5, Jerry Usary16, Zhiyuan Hu16, Karen E Rasmussen16, Laundette P Jones7, Shahin Assefnia7, Subhashini Chandrasekharan6, Michael G Backlund2, Yuzhi Yin7, Andrey I Khramtsov8, Roy Bastein9, John Quackenbush9, Robert I Glazer7, Powel H Brown10, Jeffrey E Green11, Levy Kopelovich12, Priscilla A Furth7, Juan P Palazzo13, Olufunmilayo I Olopade14, Philip S Bernard9, Gary A Churchill5, Terry Van Dyke16 and Charles M Perou1156*

Author Affiliations

1 Lineberger Comprehensive Cancer Center

2 Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA

3 Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA

4 Department of Biology and Program in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA

5 The Jackson Laboratory, Bar Harbor, ME 04609, USA

6 Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA

7 Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA

8 Department of Pathology, University of Chicago, Chicago, IL 60637, USA

9 Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84132, USA

10 Baylor College of Medicine, Houston, TX 77030, USA

11 Transgenic Oncogenesis Group, Laboratory of Cancer Biology and Genetics

12 Chemoprevention Agent Development Research Group, National Cancer Institute, Bethesda, MD 20892, USA

13 Department of Pathology, Thomas Jefferson University, Philadelphia, PA 19107, USA

14 Section of Hematology/Oncology, Department of Medicine, Committees on Genetics and Cancer Biology, University of Chicago, Chicago, IL 60637, USA

15 Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA

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Genome Biology 2007, 8:R76  doi:10.1186/gb-2007-8-5-r76

Published: 10 May 2007

Abstract

Background

Although numerous mouse models of breast carcinomas have been developed, we do not know the extent to which any faithfully represent clinically significant human phenotypes. To address this need, we characterized mammary tumor gene expression profiles from 13 different murine models using DNA microarrays and compared the resulting data to those from human breast tumors.

Results

Unsupervised hierarchical clustering analysis showed that six models (TgWAP-Myc, TgMMTV-Neu, TgMMTV-PyMT, TgWAP-Int3, TgWAP-Tag, and TgC3(1)-Tag) yielded tumors with distinctive and homogeneous expression patterns within each strain. However, in each of four other models (TgWAP-T121, TgMMTV-Wnt1, Brca1Co/Co;TgMMTV-Cre;p53+/- and DMBA-induced), tumors with a variety of histologies and expression profiles developed. In many models, similarities to human breast tumors were recognized, including proliferation and human breast tumor subtype signatures. Significantly, tumors of several models displayed characteristics of human basal-like breast tumors, including two models with induced Brca1 deficiencies. Tumors of other murine models shared features and trended towards significance of gene enrichment with human luminal tumors; however, these murine tumors lacked expression of estrogen receptor (ER) and ER-regulated genes. TgMMTV-Neu tumors did not have a significant gene overlap with the human HER2+/ER- subtype and were more similar to human luminal tumors.

Conclusion

Many of the defining characteristics of human subtypes were conserved among the mouse models. Although no single mouse model recapitulated all the expression features of a given human subtype, these shared expression features provide a common framework for an improved integration of murine mammary tumor models with human breast tumors.