Department of Pathology, Thom as Jeffe rson University, Identific ation of conserved gene expression features between murine mammary carcinoma models and human breast tumors.

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), Published: 10 May 2007 Genome Biology 2007, 8:R76 (doi:10.1186/gb-2007-8-5-r76) Received: 29 August 2006 Revised: 18 January 2007 Accepted: 10 May 2007 The electronic version of this article is the complete one and can be found online at http://genomebiology.com/2007/8/5/R76 R76.2 Genome Biology 2007, Volume 8, Issue 5, Article R76 Herschkowitz et al. http://genomebiology.com/2007/8/5/R76 Genome Biology 2007, 8:R76 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 ERregulated genes. TgMMTV-Neu tumors did not have a significant gene overlap with the human HER2+/ERsubtype 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. Background Global gene expression analyses of human breast cancers have identified at least three major tumor subtypes and a normal breast tissue group [1]. Two subtypes are estrogen receptor (ER)-negative with poor patient outcomes [2,3]; one of these two subtypes is defined by the high expression of HER2/ERBB2/NEU (HER2+/ER-) and the other shows characteristics of basal/myoepithelial cells (basal-like). The third major subtype is ER-positive and Keratin 8/18-positive, and designated the 'luminal' subtype. This subtype has been subdivided into good outcome 'luminal A' tumors and poor outcome 'luminal B' tumors [2,3]. These studies emphasize that human breast cancers are multiple distinct diseases, with each of the major subtypes likely harboring different genetic alterations and responding distinctly to therapy [4,5]. Further similar investigations may well identify additional subtypes useful in diagnosis and treatment; however, such research would be accelerated if the relevant disease properties could be accurately modeled in experimental animals. Signatures associated with specific genetic lesions and biologies can be causally assigned in such models, potentially allowing for refinement of human data. Significant progress in the ability to genetically engineer mice has led to the generation of models that recapitulate many properties of human cancers [6]. Mouse mammary tumor models have been designed to emulate genetic alterations found in human breast cancers, including inactivation of TP53, BRCA1, and RB, and overexpression of MYC and HER2/ERBB2/NEU. Such models have been generated through several strategies, including transgenic overexpression of oncogenes, expression of dominant interfering proteins, targeted disruption of tumor suppressor genes, and by treatment with chemical carcinogens [7]. While there are many advantages to using the mouse as a surrogate, there are also potential caveats, including differences in mammary physiologies and the possibility of unknown species-specific pathway differences. Furthermore, it is not always clear which features of a human cancer are most relevant for disease comparisons (for example, genetic aberrations, histological features, tumor biology). Genomic profiling provides a tool for comparative cancer analysis and offers a powerful means of cross-species comparison. Recent studies applying microarray technology to human lung, liver, or prostate carcinomas and their respective murine counterparts have reported commonalities [8-10]. In general, each of these studies focused on a single or few mouse models. Here, we used gene expression analysis to classify a large set of mouse mammary tumor models and human breast tumors. The results provide biological insights among and across the mouse models, and comparisons with human data identify biologically and clinically significant shared features. Results Murine tumor analysis To characterize the diversity of biological phenotypes present within murine mammary carcinoma models, we performed microarray-based gene expression analyses on tumors from 13 different murine models (Table 1) using Agilent microarrays and a common reference design [1]. We performed 122 microarrays consisting of 108 unique mammary tumors and 10 normal mammary gland samples (Additional data file 1). Using an unsupervised hierarchical cluster analysis of the data (Additional data file 2), murine tumor profiles indicated the presence of gene sets characteristic of endothelial cells, fibroblasts, adipocytes, lymphocytes, and two distinct epithelial cell types (basal/myoepithelial and luminal). Grouping of the murine tumors in this unsupervised cluster showed that some models developed tumors with consistent, model-specific patterns of expression, while other models showed greater diversity and did not necessarily group together. Specifically, the TgWAP-Myc, TgMMTV-Neu, TgMMTV-PyMT, TgWAP-Int3 (Notch4), TgWAP-Tag and TgC3(1)-Tag tumors had high within-model correlations. In contrast, tumors from the TgWAP-T121, TgMMTV-Wnt1, Brca1Co/ Co;TgMMTV-Cre;p53+/-, and DMBA-induced models showed diverse expression patterns. The p53-/transplant model tended to be homogenous, with 4/5 tumors grouping together, while the Brca1+/-;p53+/ionizing radiation (IR) and http://genomebiology.com/2007/8/5/R76 Genome Biology 2007, Volume 8, Issue 5, Article R76 Herschkowitz et al. R76.3