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    Research Grants Awarded

    The MCM2-7 complex and breast cancer

    Study Section:
    Tumor Cell Biology V

    Scientific Abstract:
    (a) Background: Mcm4 (Minichromosome maintenance deficient 4 homolog) encodes a subunit of the MCM2-7 complex, the replication licensing factor and presumptive replicative helicase. MCM2-7 proteins are structurally related and all are essential for eukaryotic DNA replication and thus viability. Through a process termed origin licensing, the MCM2-7 complex ensures a single duplication of the genome per cell cycle, which contributes to genome stability during DNA replication. We recovered a hypomorphic Mcm4 allele named Chaos3 (Chromosome aberrations occurring spontaneously 3) in a genetic screen for chromosome instability mutations in mice. The Mcm4Chaos3 allele encodes a point mutation and appears to destabilize the entire MCM2-7 complex, causing impaired replication. More than 80% of homozygous females succumb to mammary adenocarcinoma with a mean latency of 12 months, suggesting that the Mcm4Chaos3 mutation is highly penetrant and mammary-specific. These findings are innovative and significant, because they provide the first evidence that the normal functions of MCM2-7 complex play an important role in mammary tumor suppression. (b) Objective/Hypothesis: The objective of this proposal is to understand the pathway and characteristics of Mcm4Chaos3 mammary tumorigenesis in order to advance the understanding of breast cancer genetics. Given the properties of the Mcm4Chaos3 mice, we hypothesize that MCM genes have a role in breast tumor suppression in humans. (c) Specific Aims: 1) Identify pathogenetic characteristics of Mcm4Chaos3 mammary tumors. 2) Identify human variant MCM alleles that exhibit DNA replication defects. (d) Study Design: (1) We will characterize and classify Mcm4Chaos3 mammary tumors by histopathologic and genomic analyses. (2) To identify MCM2-7 mutations that potentially cause breast cancer, we will analyze variant alleles derived from single nucleotide polymorphisms. Using the minichromosome maintenance assay in budding yeast, we will determine DNA replication defects of these variant alleles. (e) Potential Outcomes/Benefits: Demonstration of a new genetic pathway of mammary tumorigenesis involving deregulation of the MCM complex could bring new insights into the genetic mechanisms of human breast cancer. Detailed analyses of Mcm4Chaos3 mammary tumors will validate the Mcm4Chaos3 mice as a new model for developing therapeutic treatments for breast cancer.

    Lay Abstract:
    This proposal is based on our recent discovery that the DNA replication gene Mcm4 (Minichromosome maintenance deficient 4 homolog) is a new breast cancer gene in mice. The MCM4 protein, the product of the Mcm4 gene, interacts with five other related MCM proteins, forming the MCM2-7 complex, which plays central roles in DNA replication in all eukaryotes. The major function of the MCM2-7 complex ensures that the genome is to be duplicated exactly once as cells divide. This function is important for preventing the occurrence of chromosome aberrations that could initiate the development of cancers. We identified mutant mice carrying the Mcm4 mutation named Chaos3 (Chromosome aberrations occurring spontaneously 3). Mcm4Chaos3 mutant mice exhibit a high incidence of spontaneous chromosome aberrations and more than 80% of Mcm4Chaos3 mutant females develop mammary tumors. Evidence suggests that the Mcm4Chaos3 mutation compromises the MCM2-7 complex functions, leading to defective DNA replication. These findings indicate that the normal functions of MCM2-7 complex are crucial for preventing mammary tumor formation in mice and this may be the case for humans. Therefore, we propose detailed and comprehensive analyses of Mcm4Chaos3 mammary tumors to understand the underlying mechanism and also to identify pathogenesis that is relevant to breast cancer in humans. Furthermore, we will analyze variations of MCM2-7 genes in human population for DNA replication defects to identify mutations that may increase breast cancer risk. MCM genes could be new breast cancer genes in humans, thus successful completion of our research will advance the understanding of breast cancer development. Moreover, the proposed analyses will establish Mcm4Chaos3 mice as a new animal model to study breast cancer.