Mcs5 is a mammary carcinoma susceptibility rat quantitative trait locus (QTL) that contains at least three sub-loci (Mcs5a, -5b, and -5c) which contribute to susceptibility and show epistatic interactions with one another. We have shown that Mcs5a, a non-mammary gland cell autonomous locus, is a compound QTL having two interacting elements which differentially control Fbxo10 in T cells. SNPs in human homologues of both of these two elements have each been shown to associate with breast cancer risk in women (n E 12,000). The goal of this continuation proposal is to further study the Mcs5 QTL by characterizing Mcs5c and Mcs5b.
The first aim will focus on genetic and biological studies using existing congenic recombinant rat models for the Mcs5c and Mcs5b loci. Both loci will be fine mapped to intervals below 200 Kb. We will also determine if these loci act in a mammary cell autonomous manner. Next, the reduced genomic intervals of Mcs5b and Mcs5c will be annotated by comparing the WKy and WF alleles in order to identify well-defined candidate elements within these loci which underlie their susceptibility phenotypes. The genes and organ/cell type through which each locus exerts its effect on mammary cancer susceptibility will be determined. Focusing on the identified cell type, further genetic and epigenetic differences between the WKy and WF alleles at these two loci will be annotated. Examples of methods to be used include: ChIP-CHIP;chromosome conformation capture assay (3C);resequencing areas identified as potentially functional. Selected candidate loci for Mcs5c and Mcs5b will be validated by producing and characterizing appropriate genetically engineered rat models. This project will identify and characterize novel mammary cancer risk associated alleles. Preliminary data and previous results with Mcs5a suggest that human homologues of these alleles may also contribute to breast cancer risk in humans. Finally, functional studies of the Mcs5c and Mcs5b alleles will define unique pathways involved in the etiology of breast cancer.
This project is directly relative to public health in that it will investigate unique aspects of the genetic component of breast cancer etiology. It is also possible that it will provide risk markers for human breast cancer. Broadly, it will also likely provide new insights for interpretation of the results of genome-wide association studies for common diseases.
|Henning, Amanda N; Haag, Jill D; Smits, Bart M G et al. (2016) The Non-coding Mammary Carcinoma Susceptibility Locus, Mcs5c, Regulates Pappa Expression via Age-Specific Chromatin Folding and Allele-Dependent DNA Methylation. PLoS Genet 12:e1006261|
|Sharma, Deepak; Eichelberg, Mark R; Haag, Jill D et al. (2012) Effective flow cytometric phenotyping of cells using minimal amounts of antibody. Biotechniques 53:57-60|
|Veillet, Adeline L; Haag, Jill D; Remfert, Jane L et al. (2011) Mcs5c: a mammary carcinoma susceptibility locus located in a gene desert that associates with tenascin C expression. Cancer Prev Res (Phila) 4:97-106|
|Sharma, Deepak; Smits, Bart M G; Eichelberg, Mark R et al. (2011) Quantification of epithelial cell differentiation in mammary glands and carcinomas from DMBA- and MNU-exposed rats. PLoS One 6:e26145|
|Sanders, Jennifer; Haag, Jill D; Samuelson, David J (2011) Physical confirmation and mapping of overlapping rat mammary carcinoma susceptibility QTLs, Mcs2 and Mcs6. PLoS One 6:e19891|
|Samuelson, David J; Hesselson, Stephanie E; Aperavich, Beth A et al. (2007) Rat Mcs5a is a compound quantitative trait locus with orthologous human loci that associate with breast cancer risk. Proc Natl Acad Sci U S A 104:6299-304|
|Cotroneo, M S; Merry, G M; Haag, J D et al. (2006) The Mcs7 quantitative trait locus is associated with an increased susceptibility to mammary cancer in congenic rats and an allele-specific imbalance. Oncogene 25:5011-7|
|Samuelson, David J; Aperavich, Beth A; Haag, Jill D et al. (2005) Fine mapping reveals multiple loci and a possible epistatic interaction within the mammary carcinoma susceptibility quantitative trait locus, Mcs5. Cancer Res 65:9637-42|
|Nelson, Stephanie E; Gould, Michael N; Hampton, John M et al. (2005) A case-control study of the HER2 Ile655Val polymorphism in relation to risk of invasive breast cancer. Breast Cancer Res 7:R357-64|
|Samuelson, David J; Haag, Jill D; Lan, Hong et al. (2003) Physical evidence of Mcs5, a QTL controlling mammary carcinoma susceptibility, in congenic rats. Carcinogenesis 24:1455-60|
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