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丝氨酸蛋白酶，最初在人类乳腺癌细胞系中鉴定出来，随后与乳腺癌病理学的许多方面有关。女性乳腺癌细胞中基质酶上调，其表达的增加已被证明与患者不良的结局相关。目前，尚不清楚基质酶在乳腺癌发生中起因果作用，还是主要导致癌症生长和进展的次要事件，并且其作为治疗靶标的潜力仍未受过测试。迄今为止，乳腺腺体消融的影响分析了乳腺中乳腺中的围产期致死性。但是，我们的建议提出了绕过这一限制的新技术。在我们提出的研究中，将使用平行和免费的体外和体内“功能丧失”技术来进行Matriptase在乳腺癌中作用的功能和机械表征。我们以前的研究已将GPI锚定的丝氨酸蛋白酶前列腺素确定为Matriptase蛋白水解活性的生理底物和下游效应子，我们将重点介绍该蛋白水解轴对乳腺癌生物学的潜在贡献。我们认为，这两种蛋白酶与癌症的进展之间存在显着相关性，因为我们已经证明，雌马蛋白酶和前列腺素在体内在细胞中与细胞粘附起着关键作用，并且两种蛋白质水平的变化都可以通过破坏上皮紧密连接形成和完整性而扰动这些粘附。要检验的假设是，曲霉酶通过激活前列腺素酶原发挥关键功能，而雌马蛋白蛋白/前列腺素蛋白水解途径对于乳腺癌的发生至关重要，特别是通过细胞细胞粘附的丧失，从而促进癌症中的癌发生。为了检验这一假设，我们提出了两个具体目标。在第一个目的中，将使用Matriptase和前列腺素丧失的新型遗传小鼠模型来确定胃癌/前列腺素蛋白水解轴对乳腺癌启动和进展的重要性。在第二个目的中，将研究前列腺素在细胞细胞粘附中的作用，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2D和3D细胞培养的测定法涵盖了研究人类癌性疾病的创新策略，并可能为诊断和治疗乳腺癌提供新的途径。

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.