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Comparative Study
. 2007;8(5):R76.
doi: 10.1186/gb-2007-8-5-r76.

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

Jason I Herschkowitz  1 , Karl Simin, Victor J Weigman, Igor Mikaelian, Jerry Usary, Zhiyuan Hu, Karen E Rasmussen, Laundette P Jones, Shahin Assefnia, Subhashini Chandrasekharan, Michael G Backlund, Yuzhi Yin, Andrey I Khramtsov, Roy Bastein, John Quackenbush, Robert I Glazer, Powel H Brown, Jeffrey E Green, Levy Kopelovich, Priscilla A Furth, Juan P Palazzo, Olufunmilayo I Olopade, Philip S Bernard, Gary A Churchill, Terry Van Dyke, Charles M Perou
Affiliations
Comparative Study

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

Jason I Herschkowitz et al. Genome Biol. 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.

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Figures

Figure 1
Figure 1
Mouse models intrinsic gene set cluster analysis. (a) Overview of the complete 866 gene cluster diagram. (b) Experimental sample associated dendrogram colored to indicate ten groups. (c) Luminal epithelial gene expression pattern that is highly expressed in TgMMTV-PyMT, TgMMTV-Neu, and TgWAP-myc tumors. (d) Genes encoding components of the basal lamina. (e) A second basal epithelial cluster of genes, including Keratin 5. (f) Genes expressed in fibroblast cells and implicated in epithelial to mesenchymal transition, including snail homolog 1. (g) A second mesenchymal cluster that is expressed in normals. See Additional data file 2 for the complete cluster diagram with all gene names.
Figure 2
Figure 2
Immunofluorescence staining of mouse samples for basal/myoepithelial and luminal cytokeratins. (a) Wild-type (wt) mammary gland stained for Keratins 8/18 (red) and Keratin 5 (green) shows K8/18 expression in luminal epithelial cells and K5 expression in basal/myoepithelial cells. (b-f) Mouse models that show luminal-like gene expression patterns stained with K8/18 (red) and K5 (green). (g-k) Tumor samples that show basal-like, or mixed luminal and basal characteristics by gene expression, stained for K8/18 (red) and K5 (green). (j) A subset of Brca1Co/Co;TgMMTV-Cre;p53+/-tumors showing nodules of K5/K8/18 double positive cells. (l) A splindloid tumor stained for K8/18 (red) and smooth muscle actin (green).
Figure 3
Figure 3
Unsupervised cluster analysis of the combined gene expression data for 232 human breast tumor samples and 122 mouse mammary tumor samples. (a) A color-coded matrix below the dendrogram identifies each sample; the first two rows show clinical ER and HER2 status, respectively, with red = positive, green = negative, and gray = not tested; the third row includes all human samples colored by intrinsic subtype as determined from Additional data file 6; red = basal-like, blue = luminal, pink = HER2+/ER-, yellow = claudin-low and green = normal breast-like. The remaining rows correspond to murine models indicated at the right. (b) A gene cluster containing basal epithelial genes. (c) A luminal epithelial gene cluster that includes XBP1 and GATA3. (d) A second luminal cluster containing Keratins 8 and 18. (e) Proliferation gene cluster. (f) Interferon-regulated genes. (g) Fibroblast/mesenchymal enriched gene cluster. (h) The Kras2 amplicon cluster. See Additional data file 5 for the complete cluster diagram.
Figure 4
Figure 4
Cluster analysis of mouse and human tumors using the subset of genes common to both species intrinsic lists (106 total genes). (a) Experimental sample associated dendrogram color coded according to human tumor subtype and with a matrix below showing murine tumor origins. (b) The complete 106 gene cluster diagram. (c) Close-up of genes known to be important for human basal-like tumors. (d) Close-up of genes known to be important for human luminal tumors, including ER. (e) Expression pattern of HER2/ERBB2/NEU.
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