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Carcinogenesis Advance Access published online on November 4, 2004
Carcinogenesis, doi:10.1093/carcin/bgh330
© 2004 by Oxford University Press
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Received September 1, 2004
Revised October 25, 2004
Accepted October 26, 2004

CARCINOGENESIS

Gene expression profiling of chemically-induced rat mammary gland cancer

Liang Shan 1, Minshu Yu 1, and Elizabeth G. Snyderwine 1*

1 Chemical Carcinogenesis Section, Laboratory of Experimental Carcinogenesis, National Cancer Institute, NIH, Bethesda, MD 20892

* To whom correspondence should be addressed.
Elizabeth G. Snyderwine, E-mail: elizabeth_snyderwine{at}nih.gov


  Abstract

Exposure to carcinogens through diet, air, and other means is generally regarded to influence human cancer risk, but the impact of specific environmental carcinogens on human breast cancer incidence is still unknown. We examined whether distinct chemical carcinogens induce a unique transcriptional profile in mammary gland cancer that is characteristic of the etiologic agent. Rat mammary gland cancers (N=34) were generated by various carcinogens including food-derived heterocyclic amines 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, 7,12-dimethylbenz[a]anthracene, N-nitrosomethylurea, and 4-aminobiphenyl. The histopathology of the carcinomas was graded through a modified Scarff-Bloom Richardson scheme, and the gene expression profiles in the carcinomas were evaluated on a 10K cDNA microarray. Unsupervised hierarchical clustering analysis revealed two major clusters of carcinomas irrespective of the carcinogenic agent that distinguished two groups with different histopathologic parameters (degree of differentiation, nuclear grade, mitotic activity, epithelial cell growth pattern and necrosis). Using class comparison analysis and hierarchical clustering of all carcinomas irrespective of histopathology, gene expression profiles were further shown to be statistically differentially expressed according to the carcinogenic agent. These findings indicated that the transcriptional program in carcinomas is unique for the etiologic agent and can be observed among a diverse set of carcinogens despite variations in carcinoma histopathology. The ability to use microarray analysis to discern an etiology-specific profile among a pathologically heterogenous group of breast carcinomas may ultimately be valuable for determining the role of environmental chemical carcinogens in human breast cancer risk.

Keywords: rat; breast cancer; aromatic amines; heterocyclic amines; histopathology; microarray analysis; gene expression; cancer etiology.
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