ECM MEDIATORS OF CHEMOPREVENTIVE AGENTS IN THE BREAST

乳房化学预防剂的 ECM 介质

• 批准号: 2429908
• 负责人: Pepper J Schedin
• 金额: $ 11.13万
• 依托单位: AMC CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-06-01 至 2001-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2429908
• 关键词: apoptosis; breast neoplasms; cancer prevention; carcinogenesis inhibitor; cell cycle; chemoprevention; clone cells; difluoromethylornithine; enzyme induction /repression; extracellular matrix; female; fibronectins; laboratory rat; lactation; laminin; mammary epithelium; mesenchyme; metalloendopeptidases; northern blottings; preneoplastic state; protein reconstitution; retinoids; tenascin; western blottings

We hypothesize that the chemopreventive activity of difluoromethlyornithine (DFMO) and retinoids on MNU-induced mammary carcinogenesis in the Sprague- Dawley rat is a result of changes in mammary stroma. Specifically, we propose that these agents induce stroma-dependent tissue remodeling which results in apoptotic death of mammary epithelial cells. Mammary extracellular matrix (ECM) isolated from chemopreventive agent treated rats under conditions known to induce tissue remodeling will be characterized to identify ECM components that have growth suppressive activity on premetastatic mammary epithelial cells. The characterization of biactive ECM will focus on modular glycoproteins fibronectin laminin, and tenasoin and on the enzymes that control their degradation. Reconstitution experiments with purified protein will be performed to determine cause and effect relationship between specific ECM components and induction of tissue remodeling enzymes and epithelial cell death. The results from this work will contribute directly to understanding the role of ECM in regulating apoptotic cell death in mammary epithelial cells and will elucidate whether ECM can be targeted by chemopreventive agents in order to control mammary carcinogenesis.

我们假设二氟甲基鸟苷的化学预防活性 （DFMO）和维甲酸对MNU诱导的乳腺癌发生的影响。 道利大鼠是乳腺间质变化的结果。 我们特别 提出这些药物诱导基质依赖性组织重塑， 导致乳腺上皮细胞凋亡。 乳腺 从化学预防剂处理的大鼠中分离的细胞外基质（ECM 在已知诱导组织重塑的条件下， 鉴定具有生长抑制活性ECM组分， 转移前乳腺上皮细胞。 双活性的表征 ECM将侧重于模块糖蛋白纤维连接蛋白层粘连蛋白和tenasoin 以及控制其降解的酶。 复溶 将用纯化的蛋白质进行实验以确定原因， 特定ECM成分与组织诱导之间的效应关系 重塑酶和上皮细胞死亡。 这项工作的结果 将直接有助于理解ECM在调节 乳腺上皮细胞的凋亡性细胞死亡，并将阐明是否 ECM可以被化学预防剂靶向，以控制乳腺癌的发生。 致癌作用