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.
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