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    Awarded Grants
    The Role of TP53 Mutation in Genome Stability and Chemotherapeutic Resistance in Breast Cancer

    Scientific Abstract:
    While breast cancer is one of the most common malignancies in women, it remains a difficult disease to treat, particularly in the metastatic setting, where essentially all women die from their disease. The individual variation in response to treatment is an important clinical problem. The tumor suppressor p53, critical to maintaining genome stability, plays an important role in breast cancer tumorigenesis and response to treatment. Therefore, we hypothesize that p53 mutations in breast cancer are associated with specific genetic changes that occur after exposure to chemotherapeutic agents and that these genetic changes alter subsequent response to chemotherapeutics. Specifically, we hypothesize that a lack of functional p53 in breast cancer will result in DNA copy number changes after exposure to certain cytotoxic agents and that these amplifications and deletions contain genetic alterations that confer growth advantages and resistance to apoptosis. Thus, the specific aims of this proposal are: 1) to define the effects of clinically relevant chemotherapeutic agents on genome stability of breast cancer cells and identify somatic genetic changes that occur after exposure to chemotherapeutic agents both in vitro using breast cancer cell lines and in vivo using a novel mouse model of mammary cancer; and 2) to then characterize these genetic changes in primary human breast cancers. We have a unique capability to study the genetic alterations that arise in the presence of p53 mutations in these three complimentary systems and evaluate these systems using a high-resolution genome-wide copy number assay (array comparative genomic hybridization) that avoids the inherent limitations of a candidate gene approach. This research has the potential to improve treatment options for women with breast cancer by identifying the genetic changes that enhance resistance to chemotherapy and recurrence potential. These changes in turn may be novel genetic targets for therapeutic development. Rapid dissemination of these data to the research community at large will facilitate the evaluation of these potential therapeutic targets and speed the translation from laboratory observations to effective treatments for women with breast cancer.

    Lay Abstract:
    While breast cancer is one of the most common diseases in women, it remains an elusive disease for treatment, and essentially all women with metastatic breast cancer die from their disease. A tumor suppressor gene called p53 plays a very important role in breast cancer development and response to chemotherapy. When p53 is mutated, there is an increased chance of disease recurrence and lack of response to treatment. We hypothesize that breast cancers with mutated p53 have specific genetic changes that render the patient more likely to not respond to treatment or have disease recurrence after treatment than those without mutated p53. These genetic changes may be important because they may cause the cells to be difficult to treat. Therefore, we want to identify these changes so that we may develop better treatments for the patients with these changes. We have three complimentary systems in which to study genetic changes that arise in tumors with mutated p53, as well as high-resolution genome-wide analysis tools. These systems include breast cancer cells that grow in the laboratory, a mouse model with mutated p53 that closely mimic the human disease, and breast tumors from patients. The research from this proposal has the potential to improve treatment options for women with breast cancer by identifying the genetic changes in breast cancer cells that result in resistance to chemotherapy and disease recurrence. New treatments may be developed that directly target these genetic changes and rapid disclosure of these data to the research community will help in the evaluation of the potential new targets and speed the development of more effective treatments for women with breast cancer.