Non-targeted effects of low dose ionizing radiation act via TGFβ to promote mammary carcinogenesis

It is widely believed that the carcinogenic action of ionizing radiation is due to targeted DNA damage and resulting mutations, but there is also substantial evidence that non-targeted radiation effects alter epithelial phenotype and the stromal microenvironment. Activation of transforming growth factor β1 (TGFβ) is a non-targeted radiation effect that mediates cell fate decisions following DNA damage and regulates microenvironment composition; it could either suppress or promote cancer. We asked if such non-targeted radiation effects contribute to carcinogenesis by using a novel radiation chimera model. Unirradiated Trp53 null mammary epithelium was transplanted to the mammary stroma, previously divested of endogenous epithelia, of mice previously exposed to a single low (10 -100 cGy) radiation dose. By 300 days, 100% of transplants in irradiated hosts at either 10 or 100 cGy had developed Trp53 null breast carcinomas compared to 54% in unirradiated hosts. Tumor growth rate was also increased by high, but not low, dose host irradiation. In contrast, irradiation of Tgfb1 heterozygote mice prior to transplantation failed to decrease tumor latency, or increase growth rate at any dose. Host irradiation significantly reduced the latency of invasive ductal carcinoma compared to spindle cell carcinoma. However, irradiation of either host genotype significantly increased the frequency of estrogen receptor negative tumors. These data demonstrate two concepts critical to understanding radiation risks. First, non-targeted radiation effects can significantly promote the frequency and alter the features of epithelial cancer. Second, radiation-induced TGFβ activity is a key mechanism of tumor promotion. Keywords: Differential gene expression after low dose irradiation [Samples GSM455405-GSM455421]: Two genotypes: TGBbeta1 heterozygote and wildtype mouse mammary glands. Two time points post-10cGy-irradiation per genotype (1 week, 4 weeks); control time point was 1 week post-sham-irradiation. Two or three replicates per time point. [Samples GSM691226-GSM691263, GSM691272-GSM691281] = Differential gene expression of syngeneic murine p53null tumors from irradiated hosts in the BALB/c background. Total RNA was extracted from mammary tumors derived from transplantations of non-irradiated p53null mammary fragments into irradiated hosts. We analyzed a total of 32 p53null tumors from irradiated wild type mice: 9 from sham-irradiated hosts, and 23 from irradiated hosts. We also analyzed 16 tumors from irradiated TGFb1 heterozygote hosts: 6 from sham-irradiated hosts, and 10 from irradiated hosts.