Mechanisms of Deregulation of Matriptase in Breast Cancer

乳腺癌中 Matriptase 失调的机制

• 批准号: 8212512
• 负责人: MICHAEL D JOHNSON
• 金额: $ 31.24万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8212512
• 关键词: Affinity; Animal Model; Apoptosis; Behavior; Biochemical; Biology; Blood Vessels; Breast; Breast Cancer Cell; Breast Carcinoma; Cancer Model; Cancer Prognosis; Cancer cell line; Carcinoma; Clinical; Complementary DNA; Data; Development; Disease; Distant; Enzyme Activation; Enzymes; Epithelial; Epithelial Cells; Equilibrium; Growth; Hepatocyte Growth Factor; Human; Human Cloning; Hypoxia; Immunohistochemistry; Lipoprotein (a); Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of ovary; Mammary Neoplasms; Mammary Tumorigenesis; Mammary gland; Mediating; Membrane; Methods; Microscopic; Modeling; Monoclonal Antibodies; Neoplasm Metastasis; Oncogenes; Oncogenic; Outcome; Oxygen; PAR-2 Receptor; Pathology; Pathway interactions; Patients; Peptide Hydrolases; Physiological; Play; Primary Neoplasm; Process; Prognostic Marker; Property; Protease Inhibitor; Proteins; Publishing; Regulation; Risk; Risk Factors; Role; Sampling; Serine Protease; Serum; Site; Skin; Somatic Mutation; Sphingosine; Staging; System; Tissues; Transgenic Mice; Transgenic Model; Transgenic Organisms; Tumor Suppressor Genes; Urokinase; Work; Xenograft procedure; angiogenesis; cancer cell differentiation; cancer type; carcinogenesis; cell motility; clinical material; glycosylation; hepatocyte growth factor activator-inhibitor 1; in vitro Model; in vivo; inhibitor/antagonist; insight; lymph nodes; malignant breast neoplasm; mammary gland development; matriptase; mouse model; novel; outcome forecast; overexpression; pro-hepatocyte growth factor; public health relevance; saruplase; tool; tumor; tumor progression

DESCRIPTION (provided by applicant): Matriptase is a serine protease that is expressed in the epithelial components of essentially all epithelial tissues including the mammary gland. We have shown that in these tissues, Hepatocyte Growth factor Activator Inhibitor-1 (HAI-1), a kunitz-type protease inhibitor, is required for the normal regulation of matriptase expression and activation, and is responsible for inhibiting the enzyme after it becomes activated. We and others have shown that overexpression of matriptase is a marker of poor prognosis in a variety of human cancers, including breast cancer. When overexpressed in the skin of transgenic mice, matriptase has been shown to act as an oncogene - an effect blocked by HAI-1 overexpression. Several substrates activated by matriptase are believed to be involved in carcinogenesis and/or tumor progression, such as Hepatocyte Growth Factor, or Urokinase Plasminogen Activator, however, much remains to be discovered about the role of misregulated matriptase activity in cancer, and the underlying biochemical mechanisms involved. To explore the role of the matriptase/HAI-1 system in the mammary gland we have developed two transgenic mouse models in which we can induce the overexpression of HAI-1 or matriptase in mammary epithelial tissue. Using these models we have shown that altering the matriptase/HAI-1 balance can have a profound effect on mammary gland biology, function, and carcinogenesis. These findings are consistent with our previously published studies analyzing human tumor samples which demonstrated that overexpression of matriptase is associated with poor prognosis in node-negative breast cancer. This proposal will bridge the gap between these two bodies of work by developing an integrated understanding of the role of the matriptase/HAI-1 system in mammary gland biology, carcinogenesis and tumor progression, the biochemical mechanisms involved in these processes, and the clinical implications of their disruption in breast cancer. In Aim 1 we will use our transgenic systems to study the regulation of normal mammary gland biology, mammary carcinogenesis, and metastatic tumor behavior, by the matriptase/HAI-1 system, and will study the underlying mechanisms involved. In Aim 2 we will examine the role of hypoxia and aberrant glycosylation in the aberrant regulation of matriptase activity. In aim 3 we evaluate the clinical importance of our data by integrating the findings of the previous two aims with an analysis of primary human breast tumor samples. We will evaluate the utility of matriptase and HAI-1, alone or in combination with markers of hypoxia or altered glycosylation, as prognostic markers of clinical outcome in breast cancer. We believe that these studies will highlight the importance of the matriptase/HAI-1 system in breast cancer and will provide valuable insights as to how the pathway might be targeted therapeutically. PUBLIC HEALTH RELEVANCE: Overexpression of the serine protease matriptase has been shown to be a marker of poor prognosis in several types of cancer including breast cancer, and in an animal model has been shown to act as an oncogene. Although matriptase is known to activate several proteins thought to play a role in carcinogenesis and tumor progression, much remains to be discovered about the role of this protease in carcinogenesis and the normal development and function of epithelial tissues. This proposal will make use of novel in vivo and in vitro models combined with analysis of clinical materials, to develop an integrated understanding of the role of the matriptase/HAI-1 system in normal mammary gland development, function, carcinogenesis and tumor progression, and will evaluate the utility of matriptase and HAI-1 as markers of breast cancer prognosis.

描述（由申请人提供）：基质酶是一种丝氨酸蛋白酶，在基本上所有上皮组织的上皮成分中表达，包括乳腺。我们已经表明，在这些组织中，肝细胞生长因子激活剂抑制剂-1（HAI-1）是一种kunitz型蛋白酶抑制剂，对于正常调节matriptase表达和激活是必需的，并且负责在激活后抑制酶。我们和其他人已经表明，马曲霉酶的过表达是包括乳腺癌在内的各种人类癌症中预后不良的标志。当在转基因小鼠的皮肤中过表达时，Matriptase已被证明充当癌基因 - 这种效应被HAI -1过表达阻塞。据信，几种被曲霉酶激活的底物与癌变和/或肿瘤进展有关，例如肝细胞生长因子或尿激酶纤溶酶原激活剂，但是，对于癌症中癌症中误导性的基质酶活性的作用仍有很多待发现，涉及癌症的作用，以及涉及生物化学机制的基础。为了探索Matriptase/HAI-1系统在乳腺中的作用，我们开发了两个转基因小鼠模型，在这些模型中，我们可以在乳腺上皮组织中诱导HAI-1或Matriptase的过表达。使用这些模型，我们已经表明，改变Matriptase/HAI-1平衡可以对乳腺生物学，功能和致癌作用产生深远的影响。这些发现与我们先前发表的研究分析了人类肿瘤样品的研究一致，该研究表明，雌马蛋白原的过表达与淋巴结阴性乳腺癌的预后不良有关。该提案将通过对Matriptase/HAI-1系统在乳腺生物学，癌变和肿瘤进展，这些过程中涉及的生化机制及其在乳腺癌中的临床意义中的临床意义的综合了解来弥合这两个工作体之间的差距。在AIM 1中，我们将使用转基因系统通过matriptase/hai-1系统研究正常乳腺生物学，乳腺癌发生和转移性肿瘤行为的调节，并将研究所涉及的潜在机制。在AIM 2中，我们将研究缺氧和异常糖基化在心曲霉活性异常调节中的作用。在AIM 3中，我们通过将前两个目的的发现与对原发性人类乳腺肿瘤样品进行分析来评估数据的临床重要性。我们将单独或与缺氧或糖基化改变的标志物评估Matriptase和Hai-1的实用性，作为乳腺癌临床预后的预后标志物。 我们认为，这些研究将强调乳脂蛋白酶/HAI-1系统在乳腺癌中的重要性，并将为如何以治疗方式靶向途径提供宝贵的见解。 公共卫生相关性：丝氨酸蛋白酶基质酶的过表达已被证明是包括乳腺癌在内的几种类型的癌症预后不良的标志，并且在动物模型中已被证明是癌变。尽管已知Matriptase激活几种被认为在癌变和肿瘤进展中发挥作用的蛋白质，但这种蛋白酶在癌变中的作用以及上皮组织的正常发育和功能仍有许多发现。该建议将利用新型体内和体外模型与临床材料的分析相结合，以对Matriptase/HAI-1系统在正常乳腺发育，功能，癌变和肿瘤进展中的作用进行综合理解，并将评估Matriptase和Hai-1的效用作为乳腺癌预测的标志。