Abstract
Breast cancer ranks top in the incidence among the main sites of female cancer in developed countries. The epidemiological study on atomic bomb survivors has suggested that the excess absolute risk for breast cancer incidence is higher than any other sites. Little is known, however, about the molecular mechanisms of breast cancer induction by radiation. We focused on tumor suppressor genes p15INK4b, p16INK4a and p19ARF and analyzed these genes in radiation-induced rat mammary adenocarcinoma.
Mammary carcinomas were induced by 2 Gy gamma irradiation of Sprague-Dawley (SD) rats at 3 or 7 weeks of age. Array CGH analysis revealed that homozygous and heterozygous deletions of the Cdkn2a and Cdkn2b region were observed in 2 of 14 mammary carcinomas. Cdkn2a encodes two transcripts, p16INK4a and p19ARF from overlapping reading frames, and Cdkn2b encodes p15INK4b. The expression of p15INK4b, p16INK4a and p19ARF, examined by quantitative RT-PCR, was downregulated in the carcinoma with homozygous deletion. Unexpectedly, upregulation of these genes was observed in the other mammary carcinomas compared with normal mammary tissues. No mutation was observed in these genes except for a single nucleotide polymorphism in p16INK4a. No correlation between the gene expression and protein expression of p15INK4b, p16INK4a and p19ARF was demonstrated. On the other hand, deletion of Cdkn2a and Cdkn2b region were absent in spontaneous mammary carcinomas. These results suggest that the deletion of Cdkn2a and Cdkn2b was associated with radiation exposure.
