This Article Full Text Full Text (PDF) Supplementary Data Related Article All Versions of this Article: 1940-6207.CAPR-08-0104v1 2/2/175    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Abba, M. C. Articles by Aldaz, C. M. Search for Related Content PubMed PubMed Citation Articles by Abba, M. C. Articles by Aldaz, C. M.

Identification of Modulated Genes by Three Classes of Chemopreventive Agents at Preneoplastic Stages in a p53-Null Mouse Mammary Tumor Model

Authors' Affiliations: ¹ Department of Carcinogenesis, The University of Texas M. D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas; ² Breast Center, Departments of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas; and ³ Department of Molecular Oncology, Ligand Pharmaceuticals, Inc., San Diego, California

Requests for reprints: C. Marcelo Aldaz, Department of Carcinogenesis, The University of Texas M. D. Anderson Cancer Center, Science Park-Research Division, P.O. Box 389, Smithville, TX 78957. Phone: 512-237-2403; Fax: 512-237-2475; E-mail: maaldaz{at}mdanderson.org.

Genetically engineered mouse cancer models are among the most useful tools for testing the in vivo effectiveness of the various chemopreventive approaches. The p53-null mouse model of mammary carcinogenesis was previously characterized by us at the cellular, molecular, and pathologic levels. In a companion article, Medina et al. analyzed the efficacy of bexarotene, gefitinib, and celecoxib as chemopreventive agents in the same model. Here we report the global gene expression effects on mammary epithelium of such compounds, analyzing the data in light of their effectiveness as chemopreventive agents. SAGE was used to profile the transcriptome of p53-null mammary epithelium obtained from mice treated with each compound versus controls. This information was also compared with SAGE data from p53-null mouse mammary tumors. Gene expression changes induced by the chemopreventive treatments revealed a common core of 87 affected genes across treatments (P < 0.05). The effective compounds, bexarotene and gefitinib, may exert their chemopreventive activity, at least in part, by affecting a set of 34 genes related to specific cellular pathways. The gene expression signature revealed various genes previously described to be associated with breast cancer, such as the activator protein-1 complex member Fos-like antigen 2 (Fosl2), early growth response 1 (Egr1), gelsolin (Gsn), and tumor protein translationally controlled 1 (Tpt1), among others. The concerted modulation of many of these transcripts before malignant transformation seems to be conducive to predominantly decrease cell proliferation. This study has revealed candidate key pathways that can be experimentally tested in the same model system and may constitute novel targets for future translational research.

Key Words: Chemoprevention • gene expression profile • SAGE • Bexarotene • Gefitinib • Celecoxib