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    Research Grants Awarded

    Characterization Of Emca4, A Genetic Determinant Of Mammary Cancer Susceptibility In Rat That Is Orthologous To A Determinant Of Breast Cancer Risk In Humans

    Grant Mechanism:
    Investigator Initiated Research

    Scientific Abstract:
    Scientific abstract: Physiologically relevant rat models of mammary cancer are proving invaluable for identifying the genetic, hormonal and environmental factors that influence breast cancer risk. Since first described by us in 1997, the ACI rat model of 17beta-estradiol (E2)-induced mammary cancer has been gaining wide use in the breast cancer research community as a highly relevant animal model for the study of breast cancer etiology and prevention. We have extensively characterized this model genetically and have mapped, in genetic crosses between the highly susceptible ACI rat strain and the resistant Brown Norway (BN) rat strain, a total of seven quantitative trait loci, designated Emca3 through Emca9 (Estrogen-induced mammary cancer), that determine susceptibility to E2-induced mammary cancer. The focus of this proposal is Emca4, which was mapped to the central region of rat chromosome 7 (RNO7, 143 Mb in length) defined by markers D7Rat44 (66.2 Mb) and D7Rat15 (107.4 Mb). The impact of Emca4 on mammary cancer susceptibility has been confirmed though the generation and characterization of the ACI.BN-Emca4 congenic rat strain, which carries BN alleles across the Emca4 region on the ACI genetic background. As predicted by our mapping data, the Emca4 congenic strain exhibited dramatically reduced susceptibility to E2-induced mammary cancer relative to the ACI strain. Easton et al. recently identified nine SNPs that were significantly and reproducibly associated with breast cancer in a three-stage genome-wide association study involving 21,860 breast cancer cases and 22,578 controls. These SNPs tag 8 distinct genetic loci, four of which are orthologous to Emca loci previously identified by us as genetic determinants of susceptibility to E2-induced mammary cancer. The combined data from these studies strongly suggest commonality with respect to genetic determination of mammary/breast cancer risk between our rat model and humans. One of the breast cancer-associated SNPs identified by Easton et al., rs13281615, tags a haplotype block that resides at 128.4 Mb on human chromosome 8q. The orthologous position to the block tagged by rs13281615 in the rat genome is 98.4 Mb on RNO7, which is virtually identical to the peak LRS/LOD region of Emca4. Our primary hypothesis is that the genetic variant that resides within Emca4 and determines susceptibility to E2-induced mammary cancer is orthologous to, and the functional equivalent of, the genetic determinant of breast cancer risk tagged by SNP rs13281615. Our long term objective is to identify and characterize the Emca4 determinant of mammary cancer susceptibility in the rat and define the role of the human ortholog to Emca4 as a determinant of breast cancer risk. Aim 1 is to fine map the Emca4 determinant of mammary cancer susceptibility. We will use a congenic rat based mapping approach to localize Emca4 to a minimal interval approximating 1 megabase (Mb). Aim 2 is to identify the genetic variant responsible for the impact of Emca4 on susceptibility to E2-induced mammary cancer. Expression of Emca4 candidates will be examined in the mammary gland of E2 treated ACI and BN rats to identify those genes that are expressed in a rat strain specific manner. DNA sequence of Emca4 candidates will be determined to identify functionally significant polymorphisms or mutations. Aim 3 is to define the mechanism through which Emca4 impacts mammary cancer development. Gene expression profiles will be defined for E2 treated ACI and an Emca4 congenic strain carrying BN alleles across the minimal Emca4 locus. Genes that are differentially expressed will be predictive of the mechanisms though which Emca4 determines mammary cancer susceptibility. By identifying common genetic variants that impact breast cancer risk and defining the mechanisms through which they impact risk, it should be possible to devise effective regimens for reducing breast cancer incidence in the relevant populations within the next ten years.

    Lay Abstract:
    Public abstract: Physiologically relevant rat models of mammary cancer are proving invaluable for identifying the genetic, hormonal and environmental factors that influence breast cancer risk. Since first described by us in 1997, the ACI rat model of 17beta-estradiol (E2)-induced mammary cancer has been gaining wide use in the breast cancer research community as a highly relevant animal model for the study of breast cancer etiology and prevention. We have extensively characterized this model genetically and have identified several regions of the rat genome (designated as Emca loci for Estrogen-induced mammary cancer) that harbor genes that determine susceptibility to E2-induced mammary cancer. The focus of this proposal is Emca4, which was mapped to the central region of rat chromosome 7 (RNO7). RNO7 is approximately 143 million base pairs of DNA in length (Mb). The Emca4 locus extends over 41.2 Mb, from coordinates 66.2 Mb to 107.4 Mb. The impact of Emca4 on mammary cancer susceptibility has been confirmed though the generation and characterization of a new rat strain, referred to as the ACI.BN-Emca4 (Emca4 for short) congenic rat strain. The Emca4 rat strain is genetically identical to the ACI rat strain except it carries DNA from the resistant BN rat strain in the Emca4 region of RNO7. When treated with E2, the Emca4 rat strain develops many fewer mammary cancers than ACI rats, both in terms of the number of rats that develop mammary cancer (incidence) and the number of cancers observed per rat (tumor burden). Moreover, those Emca4 rats that do develop mammary cancer when treated with E2 do so after longer periods of treatment than needed to induce mammary cancer in ACI rats. Thus, the Emca4 congenic rat strain exhibits dramatically reduced susceptibility to E2-induced mammary cancer relative to the ACI strain. A recently published study provides the first indication that the region of the human genome that is equivalent (orthologous) to the Emca4 locus in the rat harbors a significant, but presently unidentified, genetic determinant of breast cancer risk. Together, the combined data from these studies strongly suggest commonality with respect to genetic determination of mammary/breast cancer risk between our rat model and humans. Because of genetic and environmental heterogeneity, it will be very difficult to identify this genetic determinant of breast cancer risk by studying human populations. Our primary hypothesis is that the genetic variant that resides within Emca4 and determines susceptibility to E2-induced mammary cancer in the rat is orthologous to, and the functional equivalent of, the genetic determinant of breast cancer risk recently localized in humans. Our long term objective is to identify and characterize the Emca4 determinant of mammary cancer susceptibility in the rat and define the role of the human counterpart to Emca4 as a determinant of breast cancer risk. Aim 1 is to fine more precisely localize the Emca4 determinant of mammary cancer susceptibility. Additional congenic rat strains carrying small regions of BN DNA within the Emca4 region will be generated and characterized. Aim 2 is to identify the genetic variant responsible for the impact of Emca4 on susceptibility to E2-induced mammary cancer. We will identify genes that reside within Emca4 and are expressed at different level in the ACI and the Emca4 congenic rat strains. These genes and the regions surrounding these genes will be sequenced to identify changes in DNA sequence that could contribute to the differing susceptibilities of the ACI and Emca4 rat strains to mammary cancer. Aim 3 is to define the mechanism through which Emca4 impacts mammary cancer development. We will compare gene expression profiles in the mammary glands of ACI and Emca4 rats. The identities of the genes that differ in expression between these strains will be predictive of mechanisms underlying the effect of Emca4 on mammary cancer susceptibility. By using our rat models to identify common genetic variants that impact breast cancer risk and defining the mechanisms through which they impact risk and translating these findings to humans, it should be possible to devise effective regimens for reducing breast cancer incidence in the relevant populations within the next ten years.