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    Research Grants Awarded

    Genome Maintenance In Breast Cancer

    Grant Mechanism:
    Investigator Initiated Research

    Scientific Abstract:
    The DNA damage response (DDR) is a signal transduction pathway that coordinates cellular activities to maintain genome integrity and act as a barrier to cancer. The DNA damage response is particularly important in breast carcinogenesis. Mutations in the checkpoint kinases ATM and Chk2 and the DNA repair/checkpoint genes Brca1 and Bach1 predispose women to develop breast cancer. Defects in the DNA damage response facilitate both the generation and proliferation of cells containing unstable genomes. Importantly, the genome maintenance capabilities of cancer cells determine the sensitivity of these cells to many therapeutic agents. Since the DDR is activated by the deregulated cell cycles associated with cancer as well as in response to many therapeutic interventions, it may be possible to use the DDR to identify genetic alterations that drive carcinogenesis, for risk assessment, and perhaps even to evaluate therapeutic response. We hypothesize that gene alterations in the early stages of carcinogenesis promote defective DNA metabolic processes such as abnormal replication or mitosis. The DDR is activated in these circumstances to eliminate or restrain the growth of these genetically unstable cells. Biological selection of those cells that also acquire mutations in the DDR and other genome maintenance activities promotes the progression to invasive breast cancer. In some cases, the particular genetic alterations in each breast tumor that drive genomic instability will make those tumors sensitive to specific therapeutic agents. To test these hypotheses we will complete the following specific aims: (1) Identify genes that regulate genome integrity in breast epithelial cells. (2) Determine the genome maintenance functions of these breast genome maintenance (BGM) genes. Aim 1 will be accomplished with a novel genetic screen in human breast cells combined with functional annotation. Aim 2 will be completed with a series of functional assays. The goal will be to specifically identify BGM genes that promote genome stability by regulating DNA replication, mitosis, or double strand break repair. Cell based studies will test the hypothesis that BGM gene status in breast cancer cell lines predicts cellular sensitivity to therapeutic agents. Future research will determine whether the BGM genes can be used as biomarkers to direct individualized therapy.

    Lay Abstract:
    Maintenance of the genome so that an exact replica of the DNA is created and distributed during every cell division cycle is critical to prevent cancer. To meet this challenge cells must avoid or correct DNA damage. Unrepaired DNA damage causes mutations that activate oncogenes and inactivate tumor suppressor genes. The DNA damage response coordinates cellular activities that minimize these mutations and maintain genome integrity. This is particularly important to prevent breast carcinogenesis since mutations in many DNA damage response genes, including the breast and ovarian cancer susceptibility genes (Brca1 and Brca2), predispose women to breast cancer. Unfortunately, Brca mutations often cause cancers with a particularly poor prognosis. Importantly, the DNA damage response is also a critical determinant of how cells respond to many breast cancer therapies. We hypothesize that gene alterations in the early stages of cancer promote defective DNA metabolic processes such as abnormal replication or chromosome segregation. The DNA damage response is activated in these circumstances to eliminate or restrain the growth of these genetically unstable cells. Defects in the DNA damage response and other genome maintenance activities permit cell survival, growth, and progression to invasive cancer. Since the DNA damage response is activated in pre-malignant lesions and by many therapeutic interventions, it may be possible to use DNA damage response biomarkers to identify genetic alterations that drive carcinogenesis, for risk assessment, and perhaps even to evaluate therapeutic response. To test these hypotheses, we will identify changes in breast cells that challenge genome integrity, and evaluate whether these changes can be used to predict sensitivity to therapeutic agents. Many cancer therapies work by inducing DNA damage or mitotic damage that cancer cells can?t survive, in part because of a genome maintenance deficiency. Since cancer cells often have less genome maintenance capabilities than normal cells, these agents can selectively kill them. Importantly, identifying the genome maintenance problem in a specific tumor may predict the treatment that will be most effective at killing that tumor. Aim 1 of this proposal will identify genome maintenance challenges in breast tumors and aim 2 will determine if this information can be used to direct the most effective treatments to patients.