Mechanisms of Deregulation of Matriptase in Breast Cancer

乳腺癌中 Matriptase 失调的机制

• 批准号: 8606423
• 负责人: MICHAEL D JOHNSON
• 金额: $ 30.3万
• 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 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8606423
• 关键词: Affinity; Animal Model; Apoptosis; Behavior; Biochemical; Biology; Blood Vessels; Breast Cancer Cell; Breast Carcinoma; Breast Epithelial Cells; Cancer Model; Cancer Prognosis; Cancer cell line; Carcinoma; Clinical; Complementary DNA; Data; Development; Disease; Distant; Enzyme Activation; Enzymes; Epithelial; 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.

描述（由申请人提供）：Matriptase是一种丝氨酸蛋白酶，在包括乳腺在内的基本上所有上皮组织的上皮成分中表达。我们已经证明，在这些组织中，肝细胞生长因子激活剂抑制剂-1 (HAI-1)（一种 kunitz 型蛋白酶抑制剂）是正常调节 matriptase 表达和激活所必需的，并负责在该酶变成后抑制该酶。活性。我们和其他人已经证明，基质酶的过度表达是多种人类癌症（包括乳腺癌）预后不良的标志。当 matriptase 在转基因小鼠的皮肤中过度表达时，matriptase 已被证明可以充当癌基因，这种作用会被 HAI-1 过度表达所阻断。人们认为，matriptase 激活的几种底物与癌发生和/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，然而，关于错误调节的 matriptase 活性在癌症中的作用以及潜在的生化作用，仍有许多待发现。涉及的机制。为了探索matriptase/HAI-1系统在乳腺中的作用，我们开发了两种转基因小鼠模型，在其中我们可以诱导乳腺上皮组织中HAI-1或matriptase的过度表达。使用这些模型，我们已经证明，改变 matriptase/HAI-1 平衡可以对乳腺生物学、功能和癌发生产生深远的影响。这些发现与我们之前发表的分析人类肿瘤样本的研究一致，该研究表明matriptase的过度表达与淋巴结阴性乳腺癌的不良预后相关。该提案将通过对 matriptase/HAI-1 系统在乳腺生物学、癌发生和肿瘤进展中的作用、这些过程中涉及的生化机制以及临床意义的综合理解，弥合这两个工作机构之间的差距。他们对乳腺癌的破坏。在目标 1 中，我们将使用我们的转基因系统来研究 matriptase/HAI-1 系统对正常乳腺生物学、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。在目标 2 中，我们将研究缺氧和异常糖基化在 matriptase 活性异常调节中的作用。在目标 3 中，我们通过将前两个目标的发现与原发性人类乳腺肿瘤样本的分析相结合来评估数据的临床重要性。我们将评估 matriptase 和 HAI-1 单独或与缺氧或糖基化改变标记物组合作为乳腺癌临床结果的预后标记物的效用。 我们相信，这些研究将强调 matriptase/HAI-1 系统在乳腺癌中的重要性，并将为如何靶向治疗该途径提供有价值的见解。

项目成果

Pnck overexpression in HER-2 gene-amplified breast cancer causes Trastuzumab resistance through a paradoxical PTEN-mediated process.

Pnck 在 HER-2 基因扩增的乳腺癌中过度表达，通过 PTEN 介导的矛盾过程导致曲妥珠单抗耐药。

• 发表时间: 2015-04
• 影响因子: 3.8
• 作者: Deb, Tushar B;Zuo, Annie H;Barndt, Robert J;Sengupta, Surojeet;Jankovic, Radmila;Johnson, Michael D
• 通讯作者: Johnson, Michael D

Mild acidity likely accelerates the physiological matriptase autoactivation process: a comparative study between spontaneous and acid-induced matriptase zymogen activation.

温和的酸性可能会加速生理性基质酶自动激活过程：自发性和酸诱导基质酶原激活之间的比较研究。

• 发表时间: 2020-10
• 影响因子: 4.3
• 作者: Jia, Bailing;Thompson, Hamishi A;Barndt, Robert B;Chiu, Yi;Lee, Mon;Lee, See;Wang, Jehng;Tang, Hung;Lin, Chen;Johnson, Michael D
• 通讯作者: Johnson, Michael D

Increased matriptase zymogen activation by UV irradiation protects keratinocyte from cell death.

紫外线照射增加基质酶酶原的激活，保护角质形成细胞免于细胞死亡。

• 发表时间: 2016-07
• 影响因子: 4.6
• 作者: Chen, Chi;Chen, Cheng;Lai, Chih;Wu, Bai;Lee, Shiao;Johnson, Michael D;Lin, Chen;Wang, Jehng
• 通讯作者: Wang, Jehng

Targeted deletion of HAI-1 increases prostasin proteolysis but decreases matriptase proteolysis in human keratinocytes.

HAI-1 的靶向缺失会增加人角质形成细胞中前列腺素的蛋白水解作用，但会降低基质酶的蛋白水解作用。

• 发表时间: 2021-05
• 影响因子: 4.3
• 作者: Lu, Dajun D;Gu, Yayun;Li, Sheng;Barndt, Robert J;Huang, Shih;Wang, Jehng;Su, Hui Chen;Johnson, Michael D;Lin, Chen
• 通讯作者: Lin, Chen

SPINT2 mutations in the Kunitz domain 2 found in SCSD patients inactivate HAI-2 as prostasin inhibitor via abnormal protein folding and N-glycosylation.

SCSD 患者中发现的 Kunitz 结构域 2 中的 SPINT2 突变通过异常的蛋白质折叠和 N-糖基化使 HAI-2 作为前列腺素抑制剂失活。

• 发表时间: 2024-04-18
• 影响因子: 3.5
• 作者: Huang, Nanxi;Wang, Qiaochu;Bernard, Robert B;Chen, Chao;Hu, Je;Wang, Jehng;Chan, Khee;Johnson, Michael D;Lin, Chen
• 通讯作者: Lin, Chen