Abstract
Copenhagen rats are highly resistant to mammary carcinogenesis, even after treatment with chemical carcinogens and hormones; most studies indicate that this is a dominant genetic trait. To test whether this trait is also dominant after radiation exposure, we characterized the susceptibility of irradiated Copenhagen rats to mammary carcinogenesis, as well as its inheritance, and identified tumor-suppressor genes that, when inactivated or mutated, may contribute to carcinogenesis. To this end, mammary cancer-susceptible Sprague-Dawley rats, resistant Copenhagen rats, and their F1 hybrids were irradiated with 4 Gy of γ-rays, and tumor development was monitored. Copy-number variations and allelic imbalances of genomic DNA were studied using microarrays and PCR analysis of polymorphic markers. Gene expression was assessed by quantitative PCR in normal tissues and induced mammary cancers of F1 rats. Irradiated Copenhagen rats exhibited a very low incidence of mammary cancer. Unexpectedly, this resistance trait did not show dominant inheritance in F1 rats; rather, they exhibited intermediate susceptibility levels (i.e., between those of their parent strains). The susceptibility of irradiated F1 rats to the development of benign mammary tumors (i.e., fibroadenoma and adenoma) was also intermediate. Copy-number losses were frequently observed in chromosome regions 1q52-54 (24%), 2q12-15 (33%), and 3q31-42 (24%), as were focal (38%) and whole (29%) losses of chromosome 5. Some of these chromosomal regions exhibited allelic imbalances. Many cancer-related genes within these regions were downregulated in mammary tumors as compared with normal mammary tissue. Some of the chromosomal losses identified have not been reported previously in chemically induced models, implying a novel mechanism inherent to the irradiated model. Based on these findings, Sprague-Dawley × Copenhagen F1 rats offer a useful model for exploring genes responsible for radiation-induced mammary cancer, which apparently are mainly located in specific regions of chromosomes 1, 2, 3 and 5.
Highlights
Exposure to ionizing radiation is common in the modern world and can induce various types of DNA damage, including double-strand breaks
We investigated the susceptibility of irradiated COP rats to mammary cancer and compared the results with those acquired with SD and (SD×COP)F1 rats to obtain insights into the mode of inheritance
To understand the susceptibility of irradiated COP and (SD×COP)F1 rats to mammary carcinogenesis, we irradiated each of SD (n = 20), COP (n = 19), and (SD×COP)F1 (n = 29) rats with 4 Gy of γ-rays and monitored the development of palpable mammary carcinomas and benign tumors
Summary
Exposure to ionizing radiation is common in the modern world and can induce various types of DNA damage, including double-strand breaks. Epidemiological studies have been conducted on populations exposed to radiation from various sources, including atomic bombs, medical devices, nuclear industry workplaces, contaminated environments, and natural background (see [2] for an example) These studies have clarified that cancer risk increases with radiation dose in a manner compatible with a linear response, without a threshold, at low doses and low dose rates [2]. Some genetic factors that influence the risk of developing acute tissue reactions after high doses of radiation have been identified, little is known about genetic factors that interact with radiation-induced cancer [3] Clarification of such interaction would be of benefit when considering radiation use in clinical settings, as well as for the selection of emergency workers and astronauts who will be exposed to relatively high doses of radiation [3]
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