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Title: In-silico QTL mapping of postpubertal mammary ductal development in the mouse uncovers potential human breast cancer risk loci

item HADSELL, DARRYL - Children'S Nutrition Research Center (CNRC)
item HADSELL, LOUISE - Children'S Nutrition Research Center (CNRC)
item OLEA, WALTER - Children'S Nutrition Research Center (CNRC)
item RIJNKELS, MONIQUE - Texas A&M University
item CREIGHTON, CHAD - Baylor College Of Medicine
item SMYTH, IAN - Monash University
item SHORT, KIERAN - Monash University
item COX, LIZA - Seattle Children'S Research Institute
item COX, TIMOTHY - Seattle Children'S Research Institute

Submitted to: Mammalian Genome
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/3/2014
Publication Date: 1/1/2015
Citation: Hadsell, D.L., Hadsell, L.A., Olea, W., Rijnkels, M., Creighton, C.J., Smyth, I., Short, K.M., Cox, L.L., Cox, T.C. 2015. In-silico QTL mapping of postpubertal mammary ductal development in the mouse uncovers potential human breast cancer risk loci. Mammalian Genome. 26(1-2):57-79.

Interpretive Summary: There has been a major effort to identify breast cancer risk loci in humans. Along with this there have been extensive efforts to understand breast cancer biology through employing both genetically engineered mouse models and linkage mapping in specific strains. Relatively little has been done to relate natural genetic diversity in the mouse to variations in normal mammary gland development. This report demonstrates that the variation in mammary ductal development is higher than previously described in strains commonly used in breast biology. We identified two strains which displayed extreme mammary ductal development differences using 3-dimensional imaging. We also employed genome-wide association to identify quantitative trait loci that were associated with normal development. We identified 43 genes that could be linked to normal mammary gland development as well as breast cancer on the basis of their biology. This work may have long term application to lactation biology since factors that control the extent of mammary ductal development could control the overall ability of the gland to produce milk.

Technical 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 x 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 x 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.