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National Institute of Environmental Health Sciences

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Publication Detail

Title: Rat Mcs1b is concordant to the genome-wide association-identified breast cancer risk locus at human 5q11.2 and MIER3 is a candidate cancer susceptibility gene.

Authors: denDekker, Aaron D; Xu, Xin; Vaughn, M Derek; Puckett, Aaron H; Gardner, Louis L; Lambring, Courtney J; Deschenes, Lucas; Samuelson, David J

Published In Cancer Res, (2012 Nov 15)

Abstract: Low-penetrance alleles associated with breast cancer risk have been identified in population-based studies. Most risk loci contain either no or multiple potential candidate genes. Rat mammary carcinoma susceptibility 1b (Mcs1b) is a quantitative trait locus on RN02 that confers decreased susceptibility when Copenhagen (COP)-resistant alleles are introgressed into a Wistar Furth (WF)-susceptible genome. Five WF.COP congenic lines containing COP RN02 segments were compared. One line developed an average of 3.4 ± 2.0 and 5.5 ± 3.6 mammary carcinomas per rat ± SD when females were Mcs1b-resistant homozygous and Mcs1b heterozygous, respectively. These phenotypes were significantly different from susceptible genotype littermates (7.8 ± 3.1 mean mammary carcinomas per rat ± SD, P = 0.0001 and P = 0.0413, respectively). All other congenic lines tested were susceptible. Thus, Mcs1b was narrowed to 1.8 Mb of RN02 between genetic markers ENSRNOSNP2740854 and g2UL2-27. Mammary gland-graft carcinoma susceptibility assays were used to determine that donor (P = 0.0019), but not recipient Mcs1b genotype (P = 0.9381), was associated with ectopic mammary carcinoma outcome. Rat Mcs1b contains sequence orthologous to human 5q11.2, a breast cancer susceptibility locus identified in multiple genome-wide association studies. Human/rat MAP3K1/Map3k1 and mesoderm induction early response (MIER; MIER3)/MIER3 are within these orthologous segments. We identified MIER3 as a candidate Mcs1b gene based on 4.5-fold higher mammary gland levels of MIER3 transcripts in susceptible compared with Mcs1b-resistant females. These data suggest that the human 5q11.2 breast cancer risk allele marked by rs889312 is mammary gland autonomous, and MIER3 is a candidate breast cancer susceptibility gene.

PubMed ID: 22993404 Exiting the NIEHS site

MeSH Terms: Alleles; Animals; Animals, Congenic; Body Weight/genetics; Breast Neoplasms/genetics*; Cell Nucleus/genetics; Cell Nucleus/metabolism; Chromosome Mapping; Chromosomes, Human, Pair 5*; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Mammary Neoplasms, Experimental/genetics*; Nuclear Proteins/genetics*; Nuclear Proteins/metabolism; Open Reading Frames; Rats; Transcription, Genetic

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