Abstract

An important new model for the study of the inherited genetic component of breast cancer is proposed. This model is based on the WKy rat strain which is almost completely resistant to spontaneous and chemically (e.g. 7,12-dimethylbenz(a)anthracene (DMBA) and N-nitrosomethylurea (NMU)) induced mammary carcinomas. It is hypothesized based on preliminary data that the genetics underlying this resistance to mammary cancer is controlled by interacting dominant resistance and enhancer genes with the resistance gene(s) being epistatic over enhancer gene(s). The goal of this project is to identify and characterize these genes and to positionally clone the major resistance gene (likely to be Mcs-4).
The first aim i s to genetically identify the quantitative trait loci (QTLs) that control the overall susceptibility of the WKy to DMBA-induced mammary carcinomas. This information will be used in the second aim to breed and characterize two congenic rat strains, each carrying either the major resistance QTL or the major enhancer QTL. Characterization of these congenics includes the determination of whether the resistance/enhancer loci act in a cell autonomous fashion. The congenic rats will also be used in Aim 3 to identify genes that are differentially expressed between the congenic rats and the control WF rat strain. These genes will both provide hypothesis-generating data regarding gene function and an assay to screen candidate breast cancer susceptibility genes.
Aim 4 will identify (by a positional cloning approach) and evaluate candidate genes at the resistance locus (likely Mcs-4). Several novel biological assays to evaluate these potential candidates will be used. Screened candidates will be tested using transgenic rat models. Finally, human homologues will be cloned for strong candidate genes in anticipation of future human studies. The accomplishment of our goal may provide: additional insight and reagents to better estimate the genetic risk of women for breast cancer; and new targets for the development of drugs to prevent breast cancer.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA077494-02
Application #
2896435
Study Section
Chemical Pathology Study Section (CPA)
Program Officer
Yang, Shen K
Project Start
1998-07-15
Project End
2003-05-31
Budget Start
1999-06-01
Budget End
2000-05-31
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

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

  Publications

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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