Role of metalloproteinases in mammary gland remodeling

金属蛋白酶在乳腺重塑中的作用

• 批准号: 7660493
• 负责人: MINA BISSELL
• 金额: $ 55.76万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-04-15 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7660493
• 关键词: Address; Adenocarcinoma; Affect; Apoptosis; Behavior; Biochemistry; Biological; Biological Assay; Biological Process; Breast; Cancer Etiology; Cell Culture Techniques; Cell physiology; Cells; Cellular biology; Cessation of life; Development; Differentiation and Growth; Disease; Ductal; Ductal Epithelial Cell; Dysplasia; Environment; Epithelial; Epithelial Cells; Epithelial-Stromal Communication; Epithelium; Equilibrium; Extracellular Matrix; Extracellular Matrix Degradation; Functional disorder; Funding; Genes; Genomic Instability; Goals; Growth; Growth Factor; Hyperplasia; Lead; Lesion; Life; Lupus erythematosus cell; MMP3 gene; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Mechanics; Mediator of activation protein; Mesenchymal; Metalloproteases; Methods; Modeling; Molecular; Morphogenesis; Mus; Mutate; Myoepithelial cell; Neoplasms; Normal tissue morphology; Pathogenesis; Pathologic; Pathologic Processes; Pathway interactions; Phenotype; Play; Premalignant; Process; Research; Role; Series; Signal Pathway; Signal Transduction; Stem cells; Stromal Cells; Stromelysin 1; Structure-Activity Relationship; System; Testing; Therapeutic Intervention; Tissue Inhibitor of Metalloproteinase-1; Tissues; Transgenic Organisms; Transplantation; Trees; Woman; Women' s Health; base; cell behavior; cellular imaging; epithelial to mesenchymal transition; genetic manipulation; human MMP14 protein; in vivo; in vivo Model; inhibitor/antagonist; insight; intercellular communication; malignant breast neoplasm; mammary epithelium; mammary gland development; mutant; neoplastic; neoplastic cell; novel; overexpression; public health relevance; reconstitution; research study; response; tumor; tumor progression

DESCRIPTION (provided by applicant): The global objective of this research is to elucidate the molecular mechanisms underlying tissue remodeling during growth, differentiation and development in mouse mammary gland, and to gain insights into how this process goes awry in pathologic disorders, including cancer. A central issue in achieving this goal is to understand how the stromal microenvironment regulates the invasive behavior of normal epithelia during pubertal development and how mammary luminal and myoepithelial cells interact to form a stable ductal tree. Extracellular matrix (ECM)-degrading matrix metalloproteinases (MMPs) are expressed in the stroma. They play a role in normal tissue remodeling during development and also contribute to the pathogenesis of tumor progression. The present proposal addresses the mechanisms by which these stromal MMPs orchestrate the cross talk between mesenchymal and epithelial compartments. The goal for this proposal is to dissect, in molecular and cell biological detail, how MMPs affect branching morphogenesis through their ability to orchestrate the stromal microenvironment of the breast. The project will use a toolbox of genetically modified mice and mammary cells, organotypic cell culture models and in vivo transplantation systems to interrogate these models and determine the critical substrates of MMPs, what signaling pathways are regulated by MMPs and how intercellular communication is affected by MMPs. The organotypic cultures will be analyzed for growth, morphogenesis, differentiation, and invasive behavior using a combination of live cell imaging, biochemistry and cell biology. In vivo analysis will utilize genetically modified mammary glands and orthotopic transplants of mammary epithelial cells transduced with wild type and mutated MMPs, their inhibitors and substrates. The role of MMPs in fine-tuning intercellular communication during branching morphogenesis will be studied with emphasize on myoepithelial cells. The study will focus on candidate substrates in the Wnt pathway for MMP3/stromelysin, and how their cleavage by MMPs affects signaling in the mammary epithelium. By dissecting how these signaling pathways operate in balancing stem cell activation, proliferation and differentiation and the mechanical environment in the pubertal mammary gland, the applications to breast cancer should continue to unfold. These experiments will give insights into how misregulation of MMPs directly leads to the development of breast cancer. An understanding of how MMPs function in the normal tissue and how disruption of their function promotes neoplasia is necessary to achieve the long-term goal of finding cures for breast cancer. PUBLIC HEALTH RELEVANCE: Breast cancer is the second leading cause of cancer deaths in women and is the most common cancer among women. This study addresses an important aspect of women's health, of how matrix metalloproteinases regulate normal and neoplastic mammary gland function. The approaches used in this project will elucidate how MMPs alter the structural microenvironment, and how this influences the critical responses of growth and invasion in normal and abnormal mammary gland epithelium and stroma. These studies may form the basis of intervention and therapy in breast cancer, potentially in the premalignant lesions.

描述（由申请人提供）：这项研究的全球目标是阐明在生长，分化和小鼠乳腺的分化和发育过程中进行组织重塑的分子机制，并洞悉该过程如何在包括癌症在内的病理疾病中出现问题。实现这一目标的一个核心问题是了解基质微环境如何调节青春期发育过程中正常上皮的侵入性行为，以及乳腺腔内和肌上皮细胞如何相互作用以形成稳定的导管树。细胞外基质（ECM） - 降解基质金属蛋白酶（MMP）在基质中表达。它们在发育过程中在正常组织重塑中起作用，也有助于肿瘤进展的发病机理。目前的提议探讨了这些基质MMP在间质和上皮室之间协调串扰的机制。该提案的目的是通过分子和细胞生物学细节剖析MMP如何通过协调乳房基质微环境的能力来影响分支形态发生。该项目将使用遗传修饰的小鼠和乳腺细胞，器官型细胞培养模型以及体内移植系统的工具箱来询问这些模型并确定MMP的临界底物，哪些信号通路受MMPS调节以及细胞间通信如何受到MMP的影响。将使用活细胞成像，生物化学和细胞生物学的组合分析器官培养物，以分析生长，形态发生，分化和侵入性行为。体内分析将利用野生型和突变的MMPS，其抑制剂和底物转导的乳腺上皮细胞的转基因乳腺和原位移植。将研究MMP在分支形态发生过程中细胞间通信中的作用，并强调肌上皮细胞。该研究将重点关注MMP3/Stromelysin的Wnt途径中的候选底物，以及它们通过MMP的裂解如何影响乳腺上皮的信号传导。通过剖析这些信号通路在平衡干细胞激活，增殖和分化以及青春期乳腺中的机械环境中如何运作，应继续展开乳腺癌的应用。这些实验将洞悉MMP的不正调如何直接导致乳腺癌的发展。了解MMP在正常组织中的功能以及其功能的破坏如何促进肿瘤是为了实现寻找乳腺癌治疗方法的长期目标所必需的。公共卫生相关性：乳腺癌是女性癌症死亡的第二大主要原因，是女性中最常见的癌症。这项研究介绍了女性健康的一个重要方面，即基质金属蛋白酶如何调节正常和肿瘤性乳腺功能。该项目中使用的方法将阐明MMP如何改变结构微环境，以及这如何影响正常和异常乳腺上皮和基质的生长和侵袭的关键反应。这些研究可能构成乳腺癌干预和治疗的基础，这可能是在预临时病变中。