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Proteolytic matriptase-prostasin axis in breast cancer

乳腺癌中的蛋白水解基质酶-前列腺素轴

基本信息

批准号：
9228418
负责人：
Karin List
金额：
$ 6.34万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2018-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9228418
关键词：
Ablation Activator Appliances Adhesions Biological Assay Biology Breast Breast Cancer Model Breast Cancer Patient Breast Cancer cell line Breast Cancer therapy Breast Carcinogenesis Breast Carcinoma Bypass Cancerous Cell Adhesion Cell Culture System Cell surface Cell-Cell Adhesion Cells Cleaved cell Diagnosis Disease Drug Industry Enzyme Precursors Epithelial Event Extracellular Matrix Genes Genetic Goals Growth Human Impairment In Vitro Isogenic transplantation Knockout Mice Link Maintenance Malignant - descriptor Malignant Epithelial Cell Malignant Neoplasms Mammary Neoplasms Mammary gland Mediating Modeling Molecular Mouse Mammary Tumor Virus Mus Neoplasm Metastasis Oncogenic Organ PRSS8 gene Pathology Pathway interactions Patient-Focused Outcomes Peptide Hydrolases Perinatal Physiological Play Point Mutation Process Property Proteins Proteolysis Proteolytic Processing Proteomics Research Role Secondary to Serine Protease Stream Sum Techniques Testing Tight Junctions Tissues Transgenic Organisms Work base cancer cell cancer initiation carcinogenesis extracellular human disease in vivo innovation loss of function malignant breast neoplasm mammary epithelium matriptase mouse model novel therapeutic target three dimensional cell culture tool treatment strategy trypsin-like serine protease tumor tumor microenvironment tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Matriptase is a cell-surface anchored serine protease that was first identified in human breast cancer cell lines and has subsequently been implicated in many aspects of breast cancer pathology. Matriptase is up-regulated in human breast carcinoma cancer cells, and its increased expression has been shown to correlate with poor patient outcome. Presently, it is unknown if matriptase plays a causal role in breast carcinogenesis or contributes primarily to secondary events of cancer growth and progression, and its potential as a therapeutic target remains untested. Perinatal lethality in matriptase loss-of-function mice has thus far precluded analysis of the effect of matriptase ablation in the mammary gland; however our proposal presents novel techniques to bypass this limitation. In our proposed study both functional and mechanistic characterization of matriptase's role in breast cancer will be performed using parallel and complimentary in vitro and in vivo "loss-of-function" techniques. Our previous research has identified the GPI-anchored serine protease prostastin as a physiological substrate and downstream effector of matriptase proteolytic activity, and we will focus on this proteolytic axis for its potential contribution to breast cance biology. We believe there to be a significant correlation between these two proteases and cancer progression, as we have demonstrated that both matriptase and prostasin play critical roles in cell to cell adhesions in vivo, and changes in levels of either protein can perturb these adhesions via disruption of epithelial tight junction formation and integrity. The hypothesis to be tested is that matriptase exerts critical functions through activation of the prostasin zymogen and that the matriptase/prostasin proteolytic pathway is critical for breast oncogenesis, specifically through the loss of cell-cell adhesions, and thereby the promotion of carcinogenesis in vivo. To test this hypothesis, we formulated two specific aims. In the first aim the significance of the matriptase/prostasin proteolytic axis in breast cancer initiation and progression will be determined using both matriptase and prostasin loss-of-function novel genetic mouse models. In the second aim the role of prostasin in cell-cell adhesion in breast cancer will be studied with emphasis on its role in tight junction function and integrity. The combination of state-of-the art mouse genetics with 2D and 3D cell culture based assays encompasses an innovative strategy for studying human cancerous disease, and may offer new avenues for diagnosis and therapy of breast cancer.

描述（由申请人提供）：Matriptase 是一种细胞表面锚定的丝氨酸蛋白酶，首先在人乳腺癌细胞系中鉴定出，随后与乳腺癌病理学的许多方面有关。 Matriptase 在人乳腺癌细胞中表达上调，其表达增加已被证明与患者预后不良相关。目前，尚不清楚 matriptase 是否在乳腺癌发生中起因果作用，或者主要促成癌症生长和进展的继发事件，并且其作为治疗靶点的潜力尚未测试。迄今为止，matriptase 功能丧失小鼠的围产期致死率无法分析 matriptase 消融对乳腺的影响。然而，我们的提案提出了绕过这一限制的新技术。在我们提出的研究中，将使用平行且互补的体外和体内“功能丧失”技术来对基质酶在乳腺癌中的作用进行功能和机制表征。我们之前的研究已确定 GPI 锚定的丝氨酸蛋白酶前列腺素作为 matriptase 蛋白水解活性的生理底物和下游效应子，我们将重点关注该蛋白水解轴，因为它对乳腺癌生物学的潜在贡献。我们相信这两种蛋白酶与癌症进展之间存在显着相关性，因为我们已经证明，基质酶和前列腺素在体内细胞间粘附中发挥着关键作用，并且任一蛋白质水平的变化可以通过破坏上皮紧密连接的形成和完整性来扰乱这些粘附。待测试的假设是，matriptase 通过激活前列腺素酶原发挥关键功能，并且 matriptase/前列腺素蛋白水解途径对于乳腺肿瘤发生至关重要，特别是通过细胞间粘附的丧失，从而促进体内癌发生。为了检验这一假设，我们制定了两个具体目标。在第一个目标中，将使用matriptase和前列腺素功能丧失的新型遗传小鼠模型来确定matriptase/前列腺素蛋白水解轴在乳腺癌发生和进展中的重要性。第二个目标将研究前列腺素在乳腺癌细胞间粘附中的作用，重点是其在紧密连接功能和完整性中的作用。最先进的小鼠遗传学与基于 2D 和 3D 细胞培养的检测相结合，涵盖了研究人类癌症疾病的创新策略，并可能为乳腺癌的诊断和治疗提供新途径。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Bosutinib for the Treatment of Philadelphia Chromosome-Positive Leukemias.

博舒替尼用于治疗费城染色体阳性白血病。

DOI：
10.1517/21678707.2015.1036027
发表时间：
2015
期刊：
Expert opinion on orphan drugs
影响因子：
0.8
作者：
Varallo-Rodriguez,Cristina;FreyerJr,CraigW;Ontiveros,EvelenaP;Griffiths,ElizabethA;Wang,EuniceS;Wetzler,Meir
通讯作者：
Wetzler,Meir

The role of type II transmembrane serine protease-mediated signaling in cancer.