Inherited genetic susceptibility to breast cancer in women is complex and likely involves genes that contribute to both the sensitivity and resistance to this disease. Many of these potential genes, especially those contributing to resistance to breast cancer, will be difficult, if not impossible, to genetically identify in human cohorts. In contrast, such genes have been genetically identified in rodent models. The Copenhagen (COP) rat, which is almost completely resistant to mammary carcinogenesis, has been genetically analyzed. Four loci that contribute to mammary cancer susceptibility in the COP rat have recently been identified in the applicant's laboratory. They are designated as Mcs1, -2, -3, and -4 with Mcs1, -2, -3, being involved in resistance, and Mcs4 being associated with sensitivity to mammary carcinogenesis. The latter maps to a rat genomic region that is homologous to a human genomic region associated with breast cancer susceptibility in African-American women.
Under Aim 1 A, congenic rats for the COP alleles of Mcs1, -2 and -4 will be bred and characterized to measure their resistance to different classes of carcinogens and also to determine the effect of gene dosage on the associated phenotype. These rats will also be needed for Aims 2-4.
Aim 1 B will use these congenics to determine if Mcs1, -2 and -4 individually act in a cell- autonomous manner.
Aim 2 will physically locate Mcs1, -2 and -4 within a map interval of #0.5 cM. This will be accomplished by identifying and phenotyping congenic rat recombinants within a specific Mcs locus.
Under Aim 3, genes that are differentially expressed in the mammary glands of congenic rats for Mcs1, -2 and -4 when compared to mammary glands from WF rats will be identified. This will aid in defining Mcs mechanisms for both cell-autonomous and non-cell-autonomous Mcs genes. In addition, this information will be used for positional cloning a Mcs gene.
Aim 4 will focus on positionally cloning one Mcs gene, likely Mcs1. Candidate gene fragments (CGFs) will be isolated from a PAC contig relying mainly on cDNA hybrid-selection methods. CGFs will be characterized using a series of in vitro and in vivo assays. Final testing will be accomplished using rat transgenics. Cloning such a rodent gene should allow for the identification of its human homologue which can then be tested for its potential role in the susceptibility of women to breast cancer. Such a gene also may serve as a target for the development of chemoprevention agents.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA028954-21
Application #
6512574
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Yang, Shen K
Project Start
1993-07-01
Project End
2003-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
21
Fiscal Year
2002
Total Cost
$372,061
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
Smits, Bart M G; Haag, Jill D; Rissman, Anna I et al. (2013) The gene desert mammary carcinoma susceptibility locus Mcs1a regulates Nr2f1 modifying mammary epithelial cell differentiation and proliferation. PLoS Genet 9:e1003549
Leng, Ning; Dawson, John A; Thomson, James A et al. (2013) EBSeq: an empirical Bayes hierarchical model for inference in RNA-seq experiments. Bioinformatics 29:1035-43
Gould, Michael N (2009) The utility of comparative genetics to inform breast cancer prevention strategies. Genetics 183:409-12
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
Zan, Yunhong; Haag, Jill D; Chen, Kai-Shun et al. (2003) Production of knockout rats using ENU mutagenesis and a yeast-based screening assay. Nat Biotechnol 21:645-51
Haag, Jill D; Shepel, Laurie A; Kolman, Bradley D et al. (2003) Congenic rats reveal three independent Copenhagen alleles within the Mcs1 quantitative trait locus that confer resistance to mammary cancer. Cancer Res 63:5808-12
Kendziorski, C M; Newton, M A; Lan, H et al. (2003) On parametric empirical Bayes methods for comparing multiple groups using replicated gene expression profiles. Stat Med 22:3899-914
Watson, Philip A; Kim, Kwanghee; Chen, Kai-Shun et al. (2002) Androgen-dependent mammary carcinogenesis in rats transgenic for the Neu proto-oncogene. Cancer Cell 2:67-79
Shepel, L A; Gould, M N (1999) The genetic components of susceptibility to breast cancer in the rat. Prog Exp Tumor Res 35:158-69
Shepel, L A; Lan, H; Haag, J D et al. (1998) Genetic identification of multiple loci that control breast cancer susceptibility in the rat. Genetics 149:289-99

Showing the most recent 10 out of 37 publications