AGE, CELL CYCLE MARKERS AND BREAST CANCER OUTCOMES

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My academic career goal is to develop a multidisciplinary, patient-oriented research program to study the complex biologic, genetic and clinical factors that determine prognosis in patients with breast cancer, to improve the ability to predict an individual's response to standard treatment approaches, and to translate this knowledge to the development of new therapeutic and cancer control strategies. The Mentored Patient-Oriented Research Career Development Award will provide me with the means to take two important steps in implementing this goal. First, I will obtain additional education in cancer pathobiology and practical experience in molecular genetics that will augment previous training in clinical oncology, epidemiology and biostatistics. Second, I will undertake a research program that utilizes a multidisciplinary, patient-oriented approach to better understand breast cancer prognostic and predictive markers, and translate this knowledge to the clinical setting. The unifying hypothesis underlying the proposed research is that biological mechanisms of tumor development, growth and proliferation are influenced by clinical patient characteristics and that these mechanisms, in turn, result in distinct tumor behaviors that impact response to therapy and clinical patient outcomes. Earlier studies have demonstrated the prognostic and predictive significance associated with estrogen receptor expression and c-erb B2 (Her 2/neu) overexpression in breast tumors, suggesting links between a patient's clinical characteristics, the occurrence of a specific cancer phenotype and the reduced efficacy of adjuvant therapy. Two studies are proposed here to test this hypothesis in the context of another potentially important biological mechanism in breast cancer biology: dysregulation of cell cycle control. Biomarkers of cell cycle control ("cell cycle markers"), including proteins p53, p21, p27, cyclin D1 and cyclin E will be measured in a population of patients with early breast cancer. Biomarker expression will be measured by immunohistochemical staining of primary tumor tissue. In the first study, a cross-sectional design will be utilized to determine a) whether alterations in the expression of cell cycle markers are associated with age or menopausal status at diagnosis, and b) whether alterations in the expression of cell cycle makers are associated with the presence of other molecular prognostic markers. The results of the cross-sectional study will contribute information about the role of this mechanism in further explaining the differences in breast cancer biology by age. In the second study, a prospective observational cohort design will be utilized to determine whether the presence of alterations in cell cycle markers are associated with a) an increased overall risk of breast cancer recurrence or b) an earlier time to recurrence than that seen in women without this phenotype. The results of the cohort study will contribute to understanding whether cell cycle markers can identify a group of breast cancer patients at high risk of recurrence with standard treatment approaches, in whom new therapeutic strategies should be targeted.