title: DNA copy number aberrations and disruption of the p16Ink4a/Rb pathway in radiation-induced and spontaneous rat mammary carcinomas.
abstract: Chromosomal amplifications and deletions are thought to be important events in spontaneous and radiation-induced carcinogenesis. To clarify how ionizing radiation induces mammary carcinogenesis, we characterized genomic copy number aberrations for gamma-ray-induced rat mammary carcinomas using microarray-based comparative genomic hybridization. We examined 14 carcinomas induced by gamma radiation (2 Gy) and found 26 aberrations, including trisomies of chromosomes 4 and 10 for three and one carcinomas, respectively, an amplification of the chromosomal region 1q12 in two carcinomas, and deletions of the chromosomal regions 3q35q36, 5q32 and 7q11 in two, two and four carcinomas, respectively. These aberrations were not observed in seven spontaneous mammary carcinomas. The expression of p16Ink4a and p19Arf, which are located in the chromosomal region 5q32, was always up-regulated except for a carcinoma with a homozygous deletion of region 5q32. The up-regulation was not accounted for by gene mutations or promoter hypomethylation. However, the amounts of Rb and its mRNA were down-regulated in these carcinomas, indicating a disruption of the p16Ink4a/Rb pathway. This is the first report of array CGH analysis for radiation-induced mammary tumors, which reveals that they show distinct DNA copy number aberration patterns that are different from those of spontaneous tumors and those reported previously for chemically induced tumors.
authors.affiliation: Experimental Radiobiology for Children's Health Research Group, Research Center for Radiation Protection, National Institute of Radiological Sciences, Chiba, 263-8555, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Iizuka
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Imaoka
authors.forename: Takashi
authors.initials: T
authors.lastname: Takabatake
authors.forename: Mayumi
authors.initials: M
authors.lastname: Nishimura
authors.forename: Shizuko
authors.initials: S
authors.lastname: Kakinuma
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Nishimura
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Shimada
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics; D002869:Chromosome Aberrations; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000528:radiation effects; D017931:DNA Primers; D004273:DNA, Neoplasm / Q000235:genetics* / Q000528:radiation effects; D015536:Down-Regulation; D005260:Female; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects*; D015321:Gene Rearrangement; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D015674:Mammary Neoplasms, Animal / Q000000981:diagnostic imaging* / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D011519:Proto-Oncogenes / Q000528:radiation effects; D012334:RNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D011877:Radionuclide Imaging; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D015854:Up-Regulation / Q000528:radiation effects
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D017931:DNA Primers; D004273:DNA, Neoplasm; D012334:RNA, Neoplasm