Ron Receptor Tyrosine Kinase Signaling in Breast Cancer

乳腺癌中的 Ron 受体酪氨酸激酶信号转导

• 批准号: 8597378
• 负责人: Susan E Waltz
• 金额: --
• 依托单位: CINCINNATI VA MEDICAL CENTER RESEARCH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-10-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8597378
• 关键词: Age; Animals; Biochemical; Biological; Biological Markers; Breast; Breast Cancer Cell; Breast Cancer Model; Cancer Cell Growth; Cancer Etiology; Cancer Patient; Cancer cell line; Cell Line; Cell Nucleus; Cell Survival; Cessation of life; Characteristics; Data; Death Rate; Dependence; Dependency; Diagnosis; Disease; Distant Metastasis; Epithelium; Evaluation; Exhibits; Expenditure; Fatty acid glycerol esters; Female; Functional disorder; Gene Expression; Gene Targeting; Goals; Growth; Growth and Development function; Human; In Vitro; Incidence; Institution; Kinetics; Knowledge; Laboratories; Ligands; Liver; Lung; Malignant Neoplasms; Mammary Neoplasms; Mammary Tumorigenesis; Mammary gland; Mediating; Metastatic Neoplasm to the Breast; Metastatic Neoplasm to the Lung; Modeling; Molecular; Morbidity - disease rate; Mus; Mutation; Neoplasm Metastasis; Nuclear; Nuclear Translocation; Oncogenes; Outcome; Pathway interactions; Patient Care; Patients; Phenotype; Phosphorylation; Phosphotransferases; Physiological; Prevalence; Primary Neoplasm; Property; Protein Tyrosine Kinase; Proteins; Publishing; Receptor Activation; Receptor Protein-Tyrosine Kinases; Role; Signal Pathway; Signal Transduction; Site; Skin Cancer; Specimen; Testing; Transcriptional Activation; Transformed Cell Line; Transgenic Mice; Transgenic Organisms; Transplantation; Tumor Cell Line; Tumor-Derived; Tyrosine; Tyrosine Phosphorylation; United States Department of Veterans Affairs; Up-Regulation; Woman; aging population; anticancer research; base; beta catenin; breast tumorigenesis; cell transformation; clinically relevant; cohort; combat; immortalized cell; in vivo; macrophage stimulating protein; malignant breast neoplasm; mammary epithelium; migration; mutant; new therapeutic target; novel; novel therapeutics; outcome forecast; overexpression; public health relevance; receptor; response; tumor; tumor growth; tumor initiation; tumorigenesis

DESCRIPTION (provided by applicant): The Ron receptor tyrosine kinase has recently been shown to be overexpressed and activated in a cohort of human cancers, with the most compelling data found in breast cancer. Ron is overexpressed in approximately 50% of human breast cancers, and has been shown to be an independent predictor of both metastases and poor prognosis in women with this disease. While Ron overexpression appears to be an important factor in human breast cancer and metastasis, a significant gap exists in our knowledge about the signaling pathways that Ron activates in breast tumors, and about the importance of these pathways with respect to overall tumor growth and metastatic dissemination. Studies from our laboratory have shown that Ron overexpression selectively in the mammary epithelium leads to mammary tumorigenesis in female mice with 100% incidence and is associated with a high degree of breast cancer metastasis to the liver and lungs. In this model, mammary tumorigenesis is associated with elevated expression of Ron, increased receptor phosphorylation and increased Ron-associated tyrosine kinase activity. However, the degree of dependency of the Ron ligand, hepatocyte growth factor-like protein (HGFL), in this model remains unknown. Biochemical analyses of primary mammary tumors from these mice demonstrate that Ron overexpression is associated with elevated levels of tyrosine phosphorylated 2-catenin and with the upregulation of downstream 2-catenin target genes. Similar to Ron, 2-catenin expression is also associated with poor prognosis in breast cancer patients. Moreover, our preliminary data show an association between high Ron expression and high2-catenin levels in human breast cancer specimens. We also show that HGFL-induced Ron activation in human breast cancer cell lines induces rapid 2-catenin accumulation and tyrosine phosphorylation of2-catenin that is translocated to the nucleus. Based on our preliminary and published data we hypothesize that ligand-mediated activation of Ron augments 2-catenin signaling, leading to increased breast cancer growth, survival, and metastatic dissemination. To test this hypothesis three Specific Aims are proposed: (i) to delineate the role of the Ron ligand, HGFL, in breast cancer cell growth, survival and metastatic dissemination in vivo; (ii) to examine the in vivo biological significance of2-catenin expression in Ron-mediated mammary tumorigenesis and metastasis, and (iii) to determine the association, mechanism, and biological relevance of HGFL-induced, Ron-dependent 2-catenin tyrosine phosphorylation in breast cancer cells. In total, the studies outlined in this proposal will be the first to directly test the significance of ligand-induced Ron receptor activation during tumorigenesis as well as to define the molecular cross-talk between the Ron and 2-catenin signaling pathways in breast cancer. We will utilize cutting edge in vivo approaches involving the conditional loss of2-catenin, or a gene targeted loss of the Ron ligand, in the presence of Ron oncogene overexpression to analyze spontaneous breast tumor formation and metastasis in a clinically relevant murine model. PUBLIC HEALTH RELEVANCE: Excluding skin cancer, breast cancer is the most common cancer in women and is the second leading cause of cancer death in women. Approximately 180,000 new cases of invasive cancer will be diagnosed and about 40,000 women are estimated to die of this disease. As breast cancer incidence and death rates increase with age, the prevalence and morbidity of breast cancer are likely to increase with the aging population and the Veteran's Administration's expenditures and care for patients with this disease will subsequently increase accordingly. While significant effort and advancement into the treatment of this disease have occurred at the VA and other institutions, a significant gap still exists in our knowledge of new treatment options for patients with breast cancer. The focus of this proposal is to define the role of a novel protein, termed Ron, and Ron- dependent signaling pathways as potential new therapeutic targets to combat this disease.

描述（由申请人提供）： 最近，RON受体酪氨酸激酶在人类癌症中过表达和激活，并在乳腺癌中发现了最引人注目的数据。罗恩（Ron）在大约50％的人乳腺癌中过表达，并且已被证明是这种疾病女性转移酶的独立预测因子和预后不良。尽管RON的过表达似乎是人类乳腺癌和转移的重要因素，但我们对RON在乳腺肿瘤中激活的信号传导途径以及这些途径在整体肿瘤生长和转移性传播方面的重要性的了解中存在很大的差距。我们实验室的研究表明，在乳腺上皮中有选择性地过表达乳腺癌的乳腺肿瘤发生100％发病率，并且与肝癌和肺部的高度乳腺癌转移有关。在该模型中，乳腺肿瘤发生与RON的表达升高，受体磷酸化增加并增加了与RON相关的酪氨酸激酶活性有关。然而，在该模型中，罗恩配体，肝细胞生长因子样蛋白（HGFL）的依赖程度仍然未知。对这些小鼠的原发性乳腺肿瘤的生化分析表明，RON的过表达与酪氨酸磷酸化的2-Catenin水平升高以及下游2-catenin靶基因的上调有关。与罗恩（Ron）相似，乳腺癌患者的预后不良也与预后不良有关。此外，我们的初步数据表明，人类乳腺癌标本中高RON表达与高2-catenin水平之间的关联。我们还表明，HGFL诱导的人类乳腺癌细胞系中的RON激活可诱导2-catenin的2-catenin积累和2-catenin的酪氨酸磷酸化，并转移到细胞核上。基于我们的初步和发布的数据，我们假设配体介导的RON的激活增强了2-catenin信号传导，从而导致乳腺癌的生长，生存率和转移性传播增加。为了检验该假设，提出了三个特定目标：（i）描绘罗恩配体，HGFL，在体内乳腺癌细胞生长，生存和转移性传播中的作用； （ii）检查2-catenin表达在RON介导的乳腺肿瘤发生和转移中的体内生物学意义，以及（III），以确定HGFL诱导的，RON依赖性的2-catenin酪氨酸酪氨酸磷酸化的乳腺癌细胞中HGFL诱导的HGFL诱导的相关性，机制和生物学相关性。总的来说，该提案中概述的研究将是第一个直接测试肿瘤发生过程中配体诱导的RON受体激活的重要性，并定义RON和2-catenin信号途径之间的分子串扰。在Ron Oncogene过表达的情况下，我们将利用涉及2-catenin的条件损失或靶向RON配体基因靶向损失的尖端方法，以分析临床相关的鼠模型中自发性乳腺肿瘤的形成和转移。 公共卫生相关性： 除皮肤癌外，乳腺癌是女性最常见的癌症，是女性癌症死亡的第二大原因。将诊断出大约18万例新的侵入性癌症病例，估计约有40,000例死于这种疾病。随着乳腺癌的发病率和死亡率随着年龄的增长，乳腺癌的患病率和发病率可能随着人口老龄而增加，而退伍军人政府对这种疾病患者的支出和护理随后将相应增加。尽管在VA和其他机构发生了重大的努力和进步，但在我们对乳腺癌患者的新治疗方案的了解中仍然存在很大的差距。该建议的重点是定义一种新型蛋白质的作用，称为RON，而RON依赖性信号通路则是对抗这种疾病的潜在新治疗靶标。