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 genetic diversity in mammary gland development 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 breast cancer susceptibility in humans. For about half of the traits, the observed variation among the complete set of strains in this study was greater (P<0.05) than that observed with previously studied strains or with strains that are 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 (GWAS) identified 20 mammary development QTL (Mdq). Of these, 5 were syntenic with previously reported human BrCa loci. The most highly 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 highassociation 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 genetic variation in mammary ductal development is greater than previously appreciated. They also suggest that mammary tumor latency and metastatic index may be influenced by variations in the same factors that control normal mammary ductal development and that further studies of genetically diverse mice can improve our understanding of the connection between breast development and breast cancer in humans by identifying novel susceptibility genes. HHS Public Access

Genetic variation in sensitivity to estrogens and breast cancer risk

“…Therefore, differences among strains in mammary development during puberty offers an additional approach to evaluate estrogen sensitivity and actions. A survey of mammary gland architecture was performed using 43 recombinant inbred strains of mice that comprise the Mouse Diversity Panel (Hadsell et al 2015). Tissues were evaluated during puberty (42 day old) and at maturity (12 weeks) for 15 different measures of area, branching and density of the mammary ducts.…”

“…Therefore, the genetic modifiers that regulate ductal development in mice appear to overlap with breast cancer risk loci in women. Although it is unclear whether the Mdq loci regulated by development or are dependent on estrogen exposure, A search of ChIP-seq databases for H3K4me2 binding was used to identify regulatory elements within the Mdq loci and colocalize binding of progesterone receptor within 15 (Mbp) of the loci suggesting hormonal regulation (Hadsell et al 2015). …”

“…Of these previously studied 28 strains, measures of normal branch density were available for 21. By plotting strain means, mammary ductal branch density and incidence of lung metatsatsis were found to be highly correlated (R 2 >0.7) indicating that at least a portion of the loci involved in ductal structure were related to tumor development and/or metastasis (Hadsell et al 2015). …”

“… 1 Mouse loci from Hadsell et al 2015 (Hadsell et al 2015); Human loci from Phengeni (http://www.ncbi.nlm.nih.gov/gap/phegeni), and c Michailidou et al (Michailidou et al 2015; Michailidou et al 2013) a r 2 , b Mbp d Less than 5Mbp apart; iCOGS data provide larger sample sizes …”

“… 1 Mouse loci from Hadsell et al 2015 (Hadsell et al 2015); Human loci from Phengeni (http://www.ncbi.nlm.nih.gov/gap/phegeni), and …”