Abstract 1323: Sustained activation of proliferative pathways and increased mammary gland tumorigenesis with γ radiation: A mouse model study

Abstract

Abstract Breast cancer is the second most commonly diagnosed cancer in women in the USA. The mammary gland is known to be particularly sensitive to radiation injury and persistent cellular changes are known to occur after exposure to ionizing radiation (IR). While measurable effects of IR have been observed in vitro and in vivo, the longer-term consequences still have considerable uncertainty. Delayed consequences of exposure to γ radiation including tumorigensis were compared to heavy ion radiation in wild-type C57BL/6J and in APC+/min mice. Studying heavy ion radiation has implications in two distinct fields - space missions and heavy ion radiotherapy. We used 137-Cs for γ radiation and 56-Fe as heavy ion at the NASA space radiation research laboratory at Brookhaven National Laboratory. Experiments were performed as per approved protocol and 6-8 weeks female C57BL/6J mice were irradiated with 2 to 7 Gy of γ and 56-Fe radiation. APC+/min mice were irradiated at 2 and 5 Gy of γ-rays and equitoxic doses of 56-Fe radiation using an RBE (relative biological effectiveness) of 1.25. Mammary glands were harvested from WT mice at 2 and 9 months postradiation for morphological, histological, transcriptomic, and proteomic analysis. Tumorigenesis was studied in APC+/min mice at 100 days post-radiation. Mammary gland morphology in whole mount revealed a more pronounced decrease in duct density and lateral branching in the 56-Fe exposed mice. H&E stained sections of 2 Gy at 9 months were near normal than 7 Gy γ radiation. The 56-Fe glands, in contrast, were markedly different even at 9 months and showed proliferative changes in the fatty component confirmed by Ki67 staining. With γ radiation proliferative activity was more evident in the ductal tree in a dose dependent manner. In contrast to 56-Fe radiation, transcriptomic analysis at 2 months showed increased estrogen signaling with γ radiation, which correlates with the urinary estradiol level. Expression profiles at 2 or 9 month post-radiation suggests that γ-rays causes greater upregulation of gene expression. In contrast to upregulation of mostly proliferative pathways by γ radiation, 56-Fe radiation showed upregulation of major metabolic pathways. Enhanced metabolic pathways with 56-Fe are consistent with the phenotypic changes in these mice. Sustained activation of proliferative pathways by γ radiation is consistent with tumorigensis in APC+/min mice. An average 40% of the γ irradiated Min mice had mammary tumors most of which were adenomas. Only 8 % of the 56-Fe mice had mammary tumor mostly desmoid cysts. In conclusion, γ radiation although less damaging than heavy ion radiation could have more carcinogenic potential and lower radiation doses are currently investigated. We speculate that reduced tumorigensis could be due to early apoptosis and removal of 56-Fe radiation-induced complex-damages-containing cells and will be further studied. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1323.