Stromal Epithelial Interactions in Breast Cancer

乳腺癌中的间质上皮相互作用

• 批准号: 6469436
• 负责人: GERALD R CUNHA
• 金额: $ 26.72万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6469436
• 关键词: biological signal transduction; breast neoplasms; cadherins; cell cell interaction; cell differentiation; cell growth regulation; cell population study; cell transplantation; cellular oncology; epidermal growth factor; estrogen receptors; fibroblasts; gene expression; hormone regulation /control mechanism; human tissue; hybrid cells; immunocytochemistry; integrins; laboratory mouse; mammary epithelium; microarray technology; neoplasm /cancer genetics; neoplastic transformation; organ culture; paracrine; protein structure function

DESCRIPTION: (provided by applicant) A series of experiments are proposed to test and validate the idea, that mouse mammary fibroblasts (mMgF) will provide an equivalent microenvironment for proper growth and differentiation of human breast epithelium (huBrE). Definitive proof of this idea raises the possibility of using mutant mouse mammary gland stroma to investigate paracrine pathways affecting huBrE. In addition, we will assess the effects of carcinoma-associated mammary fibroblasts (CAF) on the growth, differentiation, and ductal morphogenesis of huBrE. It is anticipated that this research program will lead to a mechanistic understanding at the cellular and molecular levels of stromal-epithelial interactions in growth, differentiation, and ductal morphogenesis of huBrE and how changes in the stroma lead to the initial stages predisposing to breast cancer. Such research may lead to the discovery of new markers for stratification of breast cancer patients and possibly new therapies. To accomplish these goals, 5 specific aims are proposed. Specific Aim #1 is an analysis of differentiation and growth of normal human breast epithelium grown in vivo in combination with fibroblasts derived from normal mouse and human mammary gland. Specific Aim #2 uses tissue recombinants composed of mutant mouse mammary fibroblasts plus human breast epithelial cells to assess the role of paracrine pathways regulating growth and differentiation of human breast epithelium. In this specific aim we will assess the role of stromal estrogen receptors and "EGF-signaling" in growth, differentiation, and ductal morphogenesis of human breast epithelium. Specific Aim #3 is a characterization of differentiation and growth response of human breast epithelium grown in association with carcinoma-associated mammary fibroblasts (CAF) of mouse and human origin focusing specifically on CAF effects on (a) epithelial differentiation and (b) growth response. Specific Aim #4 focuses on the effects of CAF on E-cadherin (E-cad) and integrin expression in human breast epithelium in vivo and vitro. We will specifically determine whether perturbation of epithelial differentiation by CAF is due to perturbation of adhesion systems such as E- and P-cadherin, intergrins or the basement membrane. Specific Aim #5 deals with identification of molecular markers unique to CAF and an investigation of the time course of change in epithelial gene expression elicited by CAF in target epithelium. To accomplish these goals we will use tissue recombinant technology, cell and organ culture, immunocytochemistry, and various molecular methodologies.

描述：（由申请人提供）提出了一系列实验 测试和验证这个想法，小鼠乳腺成纤维细胞（MMGF）将提供 与人类适当生长和分化的等效微环境 乳房上皮（Hubre）。这个想法的确定证明提高了可能性 使用突变小鼠乳腺基质研究旁分泌途径 影响哈伯。此外，我们将评估 癌相关的乳腺成纤维细胞（CAF）关于分化，分化， 和哈伯的导管形态发生。预计该研究计划 将导致在细胞和分子水平上的机械理解 在生长，分化和导管中的基质 - 上皮相互作用 源头的形态发生以及基质的变化如何导致初始阶段 易感乳腺癌。这样的研究可能导致发现新的 乳腺癌患者分层的标志物，可能是新的 疗法。为了实现这些目标，提出了5个具体目标。具体的 AIM＃1是对正常乳房的分化和生长的分析 在体内生长的上皮与源自正常的成纤维细胞结合 小鼠和人类乳腺。特定的目标＃2使用组织重组者 由突变小鼠乳腺成纤维细胞和人乳房上皮细胞组成 评估调节生长和分化的旁分泌途径的作用 人类乳房上皮。在这个具体目标中，我们将评估 在生长，分化和 人乳房上皮的导管形态发生。特定目标＃3是 人乳房的分化和生长反应的表征 与癌相关的乳腺成纤维细胞相关的上皮生长 （CAF）的小鼠和人类起源专门针对CAF对（a）的影响 上皮分化和（b）生长反应。特定目标＃4专注于 CAF对人类E-钙粘蛋白（E-CAD）和整联蛋白表达的影响 乳房上皮在体内和体外。我们将明确确定是否 CAF对上皮分化的扰动是由于扰动 粘附系统，例如E-和P-钙粘蛋白，间林或地下室 膜。特定的目标＃5涉及分子标记的识别独特的识别 CAF以及对上皮基因变化的时间过程的研究 CAF在目标上皮中引起的表达。为了实现这些目标 将使用组织重组技术，细胞和器官培养， 免疫细胞化学和各种分子方法。