Department of Cancer Biology
Animals; Breast Neoplasms; Cluster Analysis; Gene Expression Profiling; *Gene Expression Regulation, Neoplastic; Humans; Mammary Neoplasms, Experimental; Mice; Neoplasm Proteins; Oligonucleotide Array Sequence Analysis; Species Specificity
Cancer Biology | Life Sciences | Medicine and Health Sciences
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.
Herschkowitz, Jason I.; Simin, Karl; Weigman, Victor J.; Mikaelian, Igor; Usary, Jerry; Hu, Zhiyuan; Rasmussen, Karen E.; Jones, Laundette P.; Assefnia, Shahin; Chandrasekharan, Subhashini; Backlund, Michael G.; Yin, Yuzhi; Khramtsov, Andrey I.; Bastein, Roy; Quackenbush, John; Glazer, Robert I.; Brown, Powel H.; Green, Jeffrey E.; Kopelovich, Levy; Furth, Priscilla A.; Palazzo, Juan P.; Olopade, Olufunmilayo I.; Bernard, Philip S.; Churchill, Gary A.; Van Dyke, Terry; and Perou, Charles M., "Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors" (2007). Open Access Articles. 2256.