AGE, CELL CYCLE MARKERS AND BREAST CANCER OUTCOMES

我的学术生涯目标是开发一个多学科的，以患者为导向的研究计划，研究决定乳腺癌患者预后的复杂生物学，遗传学和临床因素，提高预测个人对标准治疗方法的反应的能力，并将这些知识转化为新的治疗和癌症控制策略的发展。 指导患者为导向的研究职业发展奖将为我提供在实现这一目标方面采取两个重要步骤的手段。 首先，我将获得癌症病理生物学方面的额外教育和分子遗传学方面的实践经验，这将增强我以前在临床肿瘤学、流行病学和生物统计学方面的培训。 其次，我将开展一项研究计划，利用多学科，以患者为导向的方法，以更好地了解乳腺癌预后和预测标志物，并将这些知识转化为临床环境。拟议研究的统一假设是，肿瘤发育、生长和增殖的生物学机制受到临床患者特征的影响，而这些机制反过来又导致不同的肿瘤行为，从而影响对治疗的反应和临床患者结果。 早期的研究已经证明了乳腺肿瘤中雌激素受体表达和c-erb B2（Her 2/neu）过表达的预后和预测意义，表明患者的临床特征、特定癌症表型的发生和辅助治疗疗效降低之间存在联系。 两项研究提出了在乳腺癌生物学的另一个潜在的重要的生物学机制：细胞周期控制失调的背景下测试这一假设。 将在早期乳腺癌患者群体中测量细胞周期控制的生物标志物（“细胞周期标志物”），包括蛋白质p53、p21、p27、细胞周期蛋白D1和细胞周期蛋白E。 将通过原发性肿瘤组织的免疫组织化学染色测量生物标志物表达。 在第一项研究中，将采用横断面设计来确定a）细胞周期标志物表达的改变是否与诊断时的年龄或绝经状态相关，以及B）细胞周期标志物表达的改变是否与其他分子预后标志物的存在相关。 横断面研究的结果将有助于进一步解释乳腺癌生物学随年龄的差异，这一机制的作用的信息。 在第二项研究中，将采用前瞻性观察性队列设计，以确定细胞周期标志物的改变是否与a）乳腺癌复发的总体风险增加或B）复发时间早于无此表型的女性相关。 队列研究的结果将有助于了解细胞周期标志物是否可以识别一组具有标准治疗方法复发高风险的乳腺癌患者，其中应针对新的治疗策略。

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.