title: In-silico QTL mapping of postpubertal mammary ductal development in the mouse uncovers potential human breast cancer risk loci.
abstract: Genetic background plays a dominant role in mammary gland development and breast cancer (BrCa). Despite this, the role of genetics is only partially understood. This study used strain-dependent variation in an inbred mouse mapping panel, to identify quantitative trait loci (QTL) underlying structural variation in mammary ductal development, and determined if these QTL correlated with genomic intervals conferring BrCa susceptibility in humans. For about half of the traits, developmental variation among the complete set of strains in this study was greater (P < 0.05) than that of previously studied strains, or strains in current common use for mammary gland biology. Correlations were also detected with previously reported variation in mammary tumor latency and metastasis. In-silico genome-wide association identified 20 mammary development QTL (Mdq). Of these, five were syntenic with previously reported human BrCa loci. The most significant (P = 1 × 10(-11)) association of the study was on MMU6 and contained the genes Plxna4, Plxna4os1, and Chchd3. On MMU5, a QTL was detected (P = 8 × 10(-7)) that was syntenic to a human BrCa locus on h12q24.5 containing the genes Tbx3 and Tbx5. Intersection of linked SNP (r(2) > 0.8) with genomic and epigenomic features, and intersection of candidate genes with gene expression and survival data from human BrCa highlighted several for further study. These results support the conclusion that mammary tumorigenesis and normal ductal development are influenced by common genetic factors and that further studies of genetically diverse mice can improve our understanding of BrCa in humans.
authors.affiliation: Department of Pediatrics, USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, 1100 Bates St. Suite 10072, Mail Stop: BCM-320, Houston, TX, 77030-2600, USA, dhadsell@bcm.edu.
authors.forename: Darryl L
authors.initials: DL
authors.lastname: Hadsell
authors.forename: Louise A
authors.initials: LA
authors.lastname: Hadsell
authors.forename: Walter
authors.initials: W
authors.lastname: Olea
authors.forename: Monique
authors.initials: M
authors.lastname: Rijnkels
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Creighton
authors.forename: Ian
authors.initials: I
authors.lastname: Smyth
authors.forename: Kieran M
authors.initials: KM
authors.lastname: Short
authors.forename: Liza L
authors.initials: LL
authors.lastname: Cox
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Cox
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000503:physiopathology; D002874:Chromosome Mapping; D003198:Computer Simulation; D005260:Female; D055106:Genome-Wide Association Study; D006652:Histological Techniques; D006801:Humans; D008321:Mammary Glands, Animal / Q000254:growth & development*; D051379:Mice; D008815:Mice, Inbred Strains / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics*; D013045:Species Specificity; D026801:Synteny / Q000235:genetics; D041622:Tomography, Optical