title: Identification of modulated genes by three classes of chemopreventive agents at preneoplastic stages in a p53-null mouse mammary tumor model.
abstract: 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.
authors.affiliation: Department of Carcinogenesis, The University of Texas M. D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas 78957, USA.
authors.forename: Martín C
authors.initials: MC
authors.lastname: Abba
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Hu
authors.forename: Carla C
authors.initials: CC
authors.lastname: Levy
authors.forename: Sally
authors.initials: S
authors.lastname: Gaddis
authors.forename: Frances S
authors.initials: FS
authors.lastname: Kittrell
authors.forename: Jamal
authors.initials: J
authors.lastname: Hill
authors.forename: Reid P
authors.initials: RP
authors.lastname: Bissonnette
authors.forename: Powel H
authors.initials: PH
authors.lastname: Brown
authors.forename: Daniel
authors.initials: D
authors.lastname: Medina
authors.forename: C Marcelo
authors.initials: CM
authors.lastname: Aldaz
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use; D000077610:Bexarotene; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D000068579:Celecoxib; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D000077156:Gefitinib; D020869:Gene Expression Profiling; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D011230:Precancerous Conditions / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D011720:Pyrazoles / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use*; D013449:Sulfonamides / Q000627:therapeutic use*; D013764:Tetrahydronaphthalenes / Q000627:therapeutic use*; D000090324:Tumor Protein, Translationally-Controlled 1; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: D016588:Anticarcinogenic Agents; D014408:Biomarkers, Tumor; D016861:Cyclooxygenase Inhibitors; D011720:Pyrazoles; D011799:Quinazolines; D013449:Sulfonamides; D013764:Tetrahydronaphthalenes; C000715648:Tpt1 protein, mouse; D000090324:Tumor Protein, Translationally-Controlled 1; D016159:Tumor Suppressor Protein p53; D000077610:Bexarotene; D066246:ErbB Receptors; D000068579:Celecoxib; D000077156:Gefitinib