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The genes that predispose to breast cancer development in most women with a family history of breast cancer have yet to be identified. We propose a means to identify genes that play a role in cancer development or progression. A mutant allele of the Apc gene results in an increased risk of mammary tumor development in mice. Exposure of mice carrying the mutant allele on one genetic background to a carcinogen results in over 90% of the mice developing carcinomas within 60 days. Another strain of mice carrying the mutant allele are resistant to developing mammary cancer. When these mice are treated with the carcinogen, few develop cancers. However, these mice are still susceptible to the development of hyperplastic, or benign, lesions of the mammary gland. By performing crosses of mutant mice from the susceptible strain with those from the resistant strain, we will determine the chromosomal location of the genes conferring resistance to development of cancer. We will also characterize the changes that occur during the progression from hyperplasia to neoplasia in the mammary lesions that develop in these mice. These studies will be a first step toward the identification of novel genes involved in tumor development and progression.

Mutations in APC/Apc predispose both humans and mice to multiple polyps of the colon and small intestine Min/+ mice carry a mutation at Apc and are predisposed to developing spontaneous intestinal and mammary tumors. On a C57BL/6J (B6) background Min/+ mice develop spontaneous mammary tumors at a 5% rate. When injected with ENU (ethylnitrosourea) over 80% of B6 Min/+ female mice develop mammary tumors. 1 29/SvJ x B6 F1 mice that carry the Min mutation are resistant to mammary tumor development after ENU treatment. We produced backcross mice in order to map the modifier loci causing resistance in the (129/SvJ x B6) mice. Preliminary analysis of SSLP markers spaced every 20-25 cM throughout the genome indicates the possibility of two regions that contain modifiers. One region maps to chromosome 6 near the marker D6Mit36. A congenic line ROSA26, carrying this region on chromosome 6 from 129 on a B6 background had already been established. ROSA26 mice have a LacZ insertion flanked by 129 DNA in the modifier region on chromosome 6. ROSA26 x B6 F1 Min/+ mice are resistant to mammary tumors following ENU treatment. The ROSA26 mice will be used to study the biological effects of the potential modifier.

BR CAl was identified due to an increased risk of breast and/or ovarian cancer in females who carry a mutant allele. Recently it has been proposed that BRCAl has a role in DNA damage repair. If this is the case, women with mutations in BR CA, who have only one functional allele, may have increased susceptibility to the effects of DNA damaging agents, such as ionizing radiation. This susceptibility may result in an increased mutation rate after exposure to irradiation. Planning of prevention and treatment strategies for such high risk women must include information about environmental exposures that might increase risk. Mouse models can provide a good system in which to investigate a question such as this. We propose to test for an effect of a Brcal mutation on mammary tumor development in mice with an increased susceptibility to tumor formation. Mice carrying a mutation in the Apc gene are predisposed to mammary tumor development. The number of tumor is increased by exposure to carcinogens or irradiation. We will generate mice carrying mutant alleles at both Brcal and Apc and determine the number and time to tumor after irradiation. If heterozygosity for a mutation in Brcal increases the sensitivity to the effects of irradiation, we expect that the double mutant mice would develop more tumors or more advanced tumors after irradiation than the mice carrying either mutant allele alone.

We have been using genetically predisposed mice to identify genes that can modify the risk of mammary tumor development. Apc(Min) female mice develop mammary tumors with a 5% incidence by 100 days of age. Treatment of female Mim/+ mice with ENU can increase the incidence of mammary tumors to greater than 80% within 65 days of treatment. We have characterized a congenic strain of ice that carries the ROSA26 insertion on chromosome 6, flanked by about 25 cM of DNA derived from the 129 strain. These mice are resistant to Min-induced mammary tumor development. In order to localize the locus or loci encoding the resistance, we have produced mice carrying subsets of the 129 derived DNA. Analysis of three such lines has indicated that a strong modifier maps within 2 cM of the ROSA26 insertion. We have identified further recombinant mice that should help to determine whether the modifier is separable from the ROSA26 insertion. We are also developing mice congenic or this region from the 129 strain that do not carry the ROSA26 insertion to allow us to determine whether the modifier is separable from ROSA26.