Abstract
Although two major breast cancer susceptibility genes, BRCA1 and BRCA2, have been identified accounting for 20% of breast cancer genetic risk, identification of other susceptibility genes accounting for 80% risk remains a challenge due to the complex, multi-factorial nature of breast cancer. Complexity derives from multiple genetic determinants, permutations of gene-environment interactions, along with presumptive low-penetrance of breast cancer predisposing genes, and genetic heterogeneity of human populations. As with other complex diseases, dissection of genetic determinants in animal models provides key insight since genetic heterogeneity and environmental factors can be experimentally controlled, thus facilitating the detection of quantitative trait loci (QTL). We therefore, performed the first genome-wide scan for loci contributing to radiation-induced mammary tumorigenesis in female F2-(Dahl S x R)-intercross rats. Tumorigenesis was measured as tumor burden index (TBI) after induction of rat mammary tumors at forty days of age via 127Cs-radiation. We observed a spectrum of tumor latency, size-progression, and pathology from poorly differentiated ductal adenocarcinoma to fibroadenoma, indicating major effects of gene-environment interactions. We identified two mammary tumorigenesis susceptibility quantitative trait loci (Mts-QTLs) with significant linkage: Mts-1 on chromosome-9 (LOD-2.98) and Mts-2 on chromosome-1 (LOD-2.61), as well as two Mts-QTLs with suggestive linkage: Mts-3 on chromosome-5 (LOD-1.93) and Mts-4 on chromosome-18 (LOD-1.54). Interestingly, Chr9-Mts-1, Chr5-Mts-3 and Chr18-Mts-4 QTLs are unique to irradiation-induced mammary tumorigenesis, while Chr1-Mts-2 QTL overlaps with a mammary cancer susceptibility QTL (Mcs 3) reported for 7,12-dimethylbenz-[α]antracene (DMBA)-induced mammary tumorigenesis in F2[COP x Wistar-Furth]-intercross rats. Altogether, our results suggest at least three distinct susceptibility QTLs for irradiation-induced mammary tumorigenesis not detected in genetic studies of chemically-induced and hormone-induced mammary tumorigenesis. While more study is needed to identify the specific Mts-gene variants, elucidation of specific variant(s) could establish causal gene pathways involved in mammary tumorigenesis in humans, and hence novel pathways for therapy.
Highlights
Breast cancer is one of the most prevalent female cancers in the world, affecting at least 10% of women in industrialized nations [1,2]
We performed a total genome scan for quantitative trait loci (QTL) affecting radiation-induced mammary tumorigenesis susceptibility (Mts) using 150 F2 (Dahl S x R)-intercross female rats phenotyped for tumor burden index (TBI) as the quantitative measure for tumorigenicity measuring both latency to tumor formation and number of tumors
The chromosome 9 Mts-1, chromosome 5 -Mts-3 and chromosome 18 Mts-4 QTLs represent novel QTL regions associated with mammary tumorigenesis not previously observed in other rat intercrosses of DMBA-induced and estrogen-induced mammary tumorigenesis [3]
Summary
Breast cancer is one of the most prevalent female cancers in the world, affecting at least 10% of women in industrialized nations [1,2]. Due to the complex inheritance of this disorder and genetic heterogeneous nature of human populations it has been difficult to unravel novel breast cancer susceptibility/resistance genes that could elucidate novel pathways for diagnosis, treatment and prevention of breast cancer. Of the few reported genetic studies that have been performed in animal models of mammary carcinogenesis, all have utilized the chemically-induced model as the chosen animal model system [3]. There are no reports on genetic studies performed on radiation-induced mammary carcinogenesis, despite the fact that ionizing radiation is one of the few well-characterized etiologic factors of human breast cancer [18] and the wellestablished fact that the female breast is one of the most susceptible organs to radiation-induced cancer [19,20,21,22]
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