MOLECULAR CELLULAR PREDICTORS OF BREAST CANCER PROGNOSIS

该计划代表了一种多学科的方法， 开发新的乳腺癌预后指标。 我们建议 乳腺癌的不同病程在很大程度上是 患者之间的细胞生物学的根本差异， 恶性上皮及其反应性间质。 我们的理由是， 使用模型系统的分子和细胞生物学的进展已经准备好， 直接应用于问题。 研究项目将集中在 四个方面：1）癌基因和受体激活，通过开发新的检测方法 提高c-erbB-2原癌基因的预后特异性 过度表达和雌激素受体含量的基础上的机制，介导 这些基因的异常表达; 2）遗传畸变，通过相关 预测整体水平的遗传畸变，并通过寻找新的 异常表达影响预后的基因; 细胞遗传学，利用荧光原位杂交来评估 细胞遗传学异常在乳腺癌诊断中的作用;以及4） 间质-上皮相互作用，检验癌源性 基质成纤维细胞通过以下途径促进乳腺癌侵袭 细胞外基质成分透明质酸的过度产生。 的 该计划的临床核心将继续提供项目和其他 具有外科乳房标本和细针抽吸材料的芯， 进行临床方案，并与 管理核心提供临床数据和前瞻性随访 正在分析肿瘤样本的所有患者的信息。 的 Immunopathology Core将优化免疫组织化学测定并评估 各种细胞抗原的预后意义。 细胞培养 中心将继续处理和储存分离的乳腺组织标本， 为研究项目提供培养细胞。 细胞计数和 生物统计核心将继续提供生物统计支持， 维护所有相关数据的数据库，并进行细胞计数和 细胞动力学分析。 这些分子和细胞研究将用于 优化和增强对活检材料进行的常规化验。 这些研究的结果将通过以下方式影响乳腺癌的生存率： 改善预后指标，以及通过提供新的科学 对乳腺癌病理生理学的深刻见解。

This program represents a multidisciplinary approach save towards developing new prognostic indicators for breast cancer. We suggest that the variable course of breast cancer is in large part the result of fundamental differences among patients in the cellular biology of the malignant epithelium and its reactive stroma. Our rationale is that recent advances in molecular and cell biology using model systems are ready to be applied directly to the problem. The research projects will concentrate on four areas: 1) oncogene and receptor activation, by developing new assays to improve the prognostic specificity of c-erbB-2 proto-oncogene overexpression and estrogen receptor content based on mechanisms mediating the abnormal expression of these genes; 2) genetic aberrations, by relating prognosis to overall level of genetic aberrations and by searching for new genes whose aberrant expression affects prognosis; 3) interphase cytogenetics, utilizing fluorescence in situ hybridization to evaluate the role of cytogenetic abnormalities in breast cancer prognostication; and 4) stromal-epithelial interactions, testing the hypothesis that cancer-derived stromal fibroblasts contribute to breast cancer invasiveness via overproduction of the extracellular matrix component, hyaluronic acid. The Program's Clinical Core will continue to provide the projects and the other cores with surgical breast specimens and fine needle aspiration material, to conduct the clinical protocols and in association with the Administrative Core to provide clinical data and prospective follow-up information on all patients whose tumor samples are being analyzed. The Immunopathology Core will optimize immunohistochemical assays and evaluate the prognostic significance of various cellular antigens. The Cell Culture Core will continue to process and bank dissociated breast tissue specimens, and provide cultured cells for the research projects. The Cytometry and Biostatistics Core will continue to provide biostatistical support, to maintain a database of all relevant data, and to perform cytometric and cytokinetic analyses. These molecular and cellular studies will be used to optimize and augment the routine assays being performed on biopsy material. The results from these studies will impact on breast cancer survival by improving prognostic indicators, as well as by providing new scientific insights into breast cancer pathophysiology.