ECM MEDIATORS OF CHEMOPREVENTIVE AGENTS IN THE BREAST

我们推测二氟甲基鸟氨酸的化学预防活性 DFMO和维甲酸对MNU诱发的大鼠乳腺癌的影响 Dawley大鼠是乳腺间质改变的结果。具体来说，我们 认为这些药物诱导基质依赖的组织重塑 导致乳腺上皮细胞的凋亡性死亡。乳房 化疗预防大鼠细胞外基质的分离 在已知可诱导组织重塑的情况下， 确定具有生长抑制活性的ECM组件 癌前乳腺上皮细胞。双活性的表征 ECM将专注于模块化糖蛋白、纤维连接蛋白、层粘连蛋白和Tenasoin 以及控制它们降解的酶。重建 将对纯化的蛋白质进行实验，以确定原因和 特异性细胞外基质成分与组织诱导的作用关系 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在监管中的作用 乳腺上皮细胞的凋亡性死亡，并将阐明 化学预防药物可靶向细胞外基质以控制乳腺 致癌。

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.