Functional Analysis of Histologic Grade in Breast Cancer

乳腺癌组织学分级的功能分析

• 批准号: 7048680
• 负责人: SHANAZ H DAIRKEE
• 金额: $ 26.73万
• 依托单位: CALIFORNIA PACIFIC MED CTR RES INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-04 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7048680
• 关键词: antineoplastics; breast neoplasms; cell differentiation; cell proliferation; connective tissue stroma; epithelium; gene expression; gene expression profiling; gene induction /repression; genetic transduction; histology; human tissue; microarray technology; molecular oncology; neoplasm /cancer classification /staging; neoplasm /cancer genetics; neoplasm /cancer pharmacology; neoplastic process; stromal cells; tissue /cell culture

DESCRIPTION (provided by applicant): While anti-tumor drugs, generally aimed at controlling cell proliferation, are effective in treating fast growing tumors, paradoxically many primary breast tumors are slow growing but not necessarily indolent. Thus, novel molecular targets based on biological paradigms must be identified towards the elimination of such tumors. At the microscopic level, slow growing, well to moderately differentiated tumors can be readily distinguished from fast growing, poorly differentiated tumors and are assigned different histologic grades. However, the 'histogenetic evolution' of such differences remains elusive. We propose to use a novel approach to test the hypothesis that histologic grade is the combined manifestation of global genetic changes in the 'initiated' breast epithelial cells and the ensuing 'cross talk' with the surrounding stroma during tumor progression. A molecular road map supporting this model could assist in targeting tumors of all histologic grades. A major difficulty in the pursuit of this goal is the lack of cellular models for experimental manipulation, which reflect the breadth of biological heterogeneity in breast cancer. In our previous research, we designed and implemented strategies for establishing a comprehensive resource of live epithelial and stromal cultures from cancerous breast tissue. Here, we will use this unique resource to: 1. determine grade-specific gene expression in matched tumor-derived cellular subsets, using cDNA microarrays. 2. simulate biological interactions between these subsets to study paracrine regulation of proliferation, differentiation, and response to anti-tumor agents. 3. analyze grade-specific gene function in representative cell cultures by exogenous transduction and silencing approaches. 4. evaluate temporal acquisition of grade-specific gene expression within the tumor and contiguous blocks of adjacent non-malignant tissue. Completion of these studies will lead to an improved understanding of molecular signaling within and between cellular subsets resulting in primary breast tumors with varying degrees of histological and functional aggressiveness.

描述（由申请人提供）：虽然通常旨在控制细胞增殖的抗肿瘤药物在治疗快速生长的肿瘤中是有效的，但矛盾的是，许多原发性乳腺肿瘤生长缓慢，但不一定是惰性的。 因此，新的分子靶点的基础上的生物学范式必须确定消除这种肿瘤。 在微观水平上，生长缓慢、分化良好至中度的肿瘤可以很容易地与生长快速、分化不良的肿瘤区分开来，并被分配不同的组织学级别。 然而，这种差异的“组织发生进化”仍然难以捉摸。 我们建议使用一种新的方法来检验这一假设，即组织学分级是“启动”乳腺上皮细胞中的全球遗传变化和随后的“串扰”与周围基质在肿瘤进展过程中的综合表现。 支持该模型的分子路线图可以帮助靶向所有组织学级别的肿瘤。 在追求这一目标的一个主要困难是缺乏细胞模型的实验操作，这反映了在乳腺癌的生物异质性的广度。 在我们以前的研究中，我们设计并实施了从癌性乳腺组织中建立活的上皮和基质培养物的综合资源的策略。 在这里，我们将使用这个独特的资源：1.使用cDNA微阵列确定匹配的肿瘤衍生细胞亚群中的等级特异性基因表达。2.模拟这些亚群之间的生物相互作用，以研究旁分泌调节增殖，分化和对抗肿瘤药物的反应。3.通过外源转导和沉默方法分析代表性细胞培养物中的等级特异性基因功能。4.评估肿瘤和相邻非恶性组织的连续块内等级特异性基因表达的时间采集。 这些研究的完成将导致对细胞亚群内和细胞亚群之间的分子信号传导的更好理解，从而导致具有不同程度的组织学和功能性侵袭性的原发性乳腺肿瘤。