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.

Neutron-induced Rat Mammary Carcinomas Are Mainly of Luminal Subtype and Have Multiple Copy Number Aberrations

“…Our aCGH analysis revealed copy number aberrations in mammary carcinomas of rats. The number of aberrations we detected here is greater than what we reported previously (24) possibly due to the increased number of cancer cells we isolated using laser microdissection. We found that these aberrations were present in a variety of genes that are frequently affected in human breast cancer (22), thus supporting the idea that these aberrations play important functional roles in the development of carcinomas in rats.…”

Significance of genomic instability in breast cancer in atomic bomb survivors: analysis of microarray-comparative genomic hybridization

“…However, direct comparisons of the current results with published results in aCGH are practically difficult because the results of aCGH analyses are greatly influenced by the array design and type of samples (e.g., fresh frozen or FFPE). A previous study of an aCGH analysis of radiation-induced and spontaneous rat mammary carcinoma indicated that the frequency of carcinoma having any CNA and the number of CNA in radiation-induced carcinoma were significantly greater than that observed in the spontaneous carcinoma [34]. Another study of an aCGH analysis of premenopausal breast cancers in the residents from a nuclear fallout-contaminated area in Belarus did not show any significant differences or tendencies in the average number of total DNA CNA compared with matched control cases from Western New York, even though breast cancer from Belarus had significantly more average number of gains [35].…”

Hydrogen Peroxide Enhances TGFβ-mediated Epithelial-to-Mesenchymal Transition in Human Mammary Epithelial MCF-10A Cells

“…Images were Western blotting. Western blotting was performed as previously described (17). Cells were lysed using Complete Lysis-M, EDTA-free (Roche diagnostics, Mannheim, Germany) according to manufacturer's instructions.…”