AGE, CELL CYCLE MARKERS AND BREAST CANCER OUTCOMES

我的学术生涯目标是发展一个多学科、以患者为导向的研究项目，研究决定乳腺癌患者预后的复杂生物学、遗传和临床因素，提高预测个体对标准治疗方法反应的能力，并将这些知识转化为新的治疗和癌症控制策略的发展。“以患者为导向的指导研究职业发展奖”将为我提供实现这一目标的两个重要步骤。首先，我将在癌症病理生物学和分子遗传学方面获得额外的教育和实践经验，这将增加我之前在临床肿瘤学、流行病学和生物统计学方面的培训。其次，我将进行一个研究项目，利用多学科，以患者为导向的方法来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。该研究的统一假设是，肿瘤的发展、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患者的临床结果。早期的研究表明，乳腺癌中雌激素受体表达和c- erbb B2 （Her 2/neu）过表达具有预后和预测意义，提示患者的临床特征、特定癌症表型的发生和辅助治疗效果降低之间存在联系。本文提出了两项研究，在乳腺癌生物学中另一个潜在重要的生物学机制——细胞周期控制失调的背景下验证这一假设。细胞周期控制的生物标志物（“细胞周期标志物”），包括蛋白p53， p21, p27， cyclin D1和cyclin E将在早期乳腺癌患者群体中进行测量。生物标志物的表达将通过免疫组织化学染色测定原发肿瘤组织。在第一项研究中，将采用横断面设计来确定a)细胞周期标记物表达的改变是否与诊断时的年龄或绝经状态有关，b)细胞周期标记物表达的改变是否与其他分子预后标记物的存在有关。横断面研究的结果将提供有关这一机制在进一步解释不同年龄乳腺癌生物学差异中的作用的信息。在第二项研究中，将利用前瞻性观察队列设计来确定细胞周期标记物改变的存在是否与a)乳腺癌复发的总体风险增加或b)比没有这种表型的女性更早的复发时间相关。该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采用标准治疗方法的复发风险高的乳腺癌患者，这些患者应该针对新的治疗策略。

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.