A mammary cancer resistance modifier at the McsSa locus has been localized to an approximate 11.0 Kb region on rat chromosome 5. McsSa was shown to be a compound locus consisting of two component sub-loci Mcs5a1 (32 Kb) and Mcs5a2 (84 Kb) that synthetically interact. It appears that the causative element at both sub-loci is unlikely to be a protein coding gene. Regions of the human genome orthologous to Mcs5a2 have been tested for association with breast cancer risk in two large case-control studies (n = approximately 12,000 women). A highly significant association with an SNP (SNP-3) in this region was found. The location of SNPs that are correlated to SNP-3 reduces the Mcs5a2 region to approximately 20 Kb. The goal of the current project is to identify and characterize the genomic element(s) within these loci that modify breast cancer risk and to extend our human association studies.
Aims i nclude using congenic rats to explore questions as whether Mcs5a1 and -5a2 interact in cis and trans and whether they act in a mammary cell-autonomous manner. In addition, the ability of Mcs5a to inhibit hormonally non-responsive mammary cancer will be evaluated. The epistatic interaction between the dominant resistance allele at McsSa over the dominant increased susceptibility allele at Mcs56 will be genetically dissected. Comparative genomics together with ChlP-on-CHIP experiments using multiple antibodies will be used to identify additional transcribed and non-transcribed potential McsSa candidates. Potential candidates will be characterized for differences between mammary cancer sensitive and resistant rat lines as well as human sensitive and resistant alleles. Those with differences will be elevated to candidate status. Selective candidates will be evaluated in vivo using BAG transgenic or knockout models. Human studies will evaluate SNP-marked alleles in McsSal for association with breast cancer risk. Epidemiologic studies will also be extended to determine if the SNP(s) that associates with breast cancer risk also associates with the risk for DCIS, a premalignant breast lesion. These studies will continue to provide a better understanding to the complex genetics underlying inherited risk to breast cancer. Identifying and characterizing the causative genomic elements in McsSa that lead to breast cancer resistance in humans and rats may provide unique insights into the etiology of breast cancer. Finally, the data to be generated may provide clinical markers of breast cancer risk and novel targets for chemoprevention.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA123272-05
Application #
7825389
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Okano, Paul
Project Start
2006-07-13
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2012-05-31
Support Year
5
Fiscal Year
2010
Total Cost
$414,009
Indirect Cost
Name
University of Wisconsin Madison
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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Smits, Bart M G; Traun, Benjamin D; Devries, Thomas L et al. (2012) An insulator loop resides between the synthetically interacting elements of the human/rat conserved breast cancer susceptibility locus MCS5A/Mcs5a. Nucleic Acids Res 40:132-47
Smits, Bart M G; Sharma, Deepak; Samuelson, David J et al. (2011) The non-protein coding breast cancer susceptibility locus Mcs5a acts in a non-mammary cell-autonomous fashion through the immune system and modulates T-cell homeostasis and functions. Breast Cancer Res 13:R81
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
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