1. PLoS One. 2013 Aug 14;8(8):e72143. doi: 10.1371/journal.pone.0072143. eCollection
2013.
Multiple susceptibility loci for radiation-induced mammary tumorigenesis in
F2[Dahl S x R]-intercross rats.
Herrera VL(1), Ponce LR, Ruiz-Opazo N.
Author information:
(1)Department of Medicine, Boston University School of Medicine, Boston,
Massachusetts, United States of America.
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.
PMCID: PMC3743793
PMID: 23967281 [PubMed - indexed for MEDLINE]
PUBMED: 23967281
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