Serial analysis of gene expression in normal p53 null mammary epithelium.
Much evidence has accumulated implicating the p53 gene as of importance in breast carcinogenesis. However, much still remains to be uncovered on the specific downstream pathways influenced by this important activator/repressor of transcription. This study investigated the effects of a p53 null genotype on the transcriptome of 'normal' mouse mammary epithelium using a unique in vivo model of preneoplastic transformation. We used SAGE for the comparative analysis of p53 wild type (wt) and null mammary epithelium unexposed and exposed to hormonal stimulation. Analysis of the hormone exposed samples provided a comprehensive view of the dramatic changes in gene expression as consequence of the functional differentiation of the mammary epithelium in an in vivo system. We detected the dysregulation in p53(null) epithelium of <1% of the transcriptome. Changes in expression affected not only known p53 target genes, but also several unexpected genes such as Expi (Wdnm1), Cyp1b1, Gelsolin, Ramp2 and class I MHC genes. The dysregulation of specific genes and their potential use as preneoplastic markers was further validated using an independent model of premalignant mammary outgrowth lines. This is the first study to examine the transcriptome of very early stages of preneoplastic progression in an in vivo model that mimics human breast cancer.
Aldaz
C Marcelo
CM
The University of Texas M.D. Anderson Cancer Center, Department of Carcinogenesis, Smithville, Texas, TX 78957, USA. maldaz@odin.mdacc.tmc.edu
Hu
Yuhui
Y
Daniel
Rachael
R
Gaddis
Sally
S
Kittrell
Frances
F
Medina
Daniel
D
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D065633:Cytochrome P-450 CYP1B1; D004847:Epithelial Cells / Q000502:physiology*; D020224:Expressed Sequence Tags; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D016158:Genes, p53; D006801:Humans; D008321:Mammary Glands, Animal / Q000166:cytology / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C
D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; C585498:Cyp1b1 protein, mouse; D065633:Cytochrome P-450 CYP1B1