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.
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.
authors.affiliation: Center for Genetics and Molecular Medicine, Department of Biochemistry and Molecular Biology, and James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky 40292, USA.
authors.forename: Aaron D
authors.initials: AD
authors.lastname: denDekker
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.forename: M Derek
authors.initials: MD
authors.lastname: Vaughn
authors.forename: Aaron H
authors.initials: AH
authors.lastname: Puckett
authors.forename: Louis L
authors.initials: LL
authors.lastname: Gardner
authors.forename: Courtney J
authors.initials: CJ
authors.lastname: Lambring
authors.forename: Lucas
authors.initials: L
authors.lastname: Deschenes
authors.forename: David J
authors.initials: DJ
authors.lastname: Samuelson
mesh_terms: D000483:Alleles; D000818:Animals; D020296:Animals, Congenic; D001835:Body Weight / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics*; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D002874:Chromosome Mapping; D002895:Chromosomes, Human, Pair 5; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D016366:Open Reading Frames; D051381:Rats; D014158:Transcription, Genetic
chemical_list: C578621:MIER3 protein, human; D009687:Nuclear Proteins