Novel Mechanism of Breast Cancer Growth by CXCR7

CXCR7 促进乳腺癌生长的新机制

基本信息

批准号：
8737004
负责人：
Nicole Salazar
金额：
$ 3.05万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8737004
关键词：
Aggressive behavior Apoptotic Area Binding Biological Assay Breast Breast Cancer Cell Breast Cancer Model CXC Chemokines CXCL11 gene CXCL12 gene CXCR4 Receptors CXCR4 gene Cancer Etiology Cancer cell line Cell Cycle Arrest Cell Cycle Progression Cell Proliferation Cell Survival Cell membrane Cell-Cell Adhesion Cells Cessation of life Combination Drug Therapy Data Diagnosis Disease Disease Progression Economic Burden Endothelium Environment Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Event GTP-Binding Proteins Gene Expression Goals Growth Growth Factor Growth Factor Interaction Growth Factor Receptors Health Human In Vitro Incidence Integral Membrane Protein Life Ligand Binding Ligands Ligation Link MAPK3 gene MCF7 cell Malignant Neoplasms Malignant neoplasm of prostate Mammary Gland Parenchyma Mediating Mentors Mitogen-Activated Protein Kinases Modeling Molecular Nature Neoplasm Metastasis Normal tissue morphology Organ Pathway interactions Phosphorylation Physiological Play Property Proteins RNA Interference Receptor Activation Regulation Relative (related person)Reporting Research Research Personnel Research Training Role S Phase Site Site-Directed Mutagenesis Stromal Cell-Derived Factor 1 Techniques Testing Training Tumor Cell Line United States Woman anticancer research base career cell growth cell motility chemokine chemokine receptor chemotherapy combat cyclin B1 improved in vivo inhibitor/antagonist insight mRNA Expression malignant breast neoplasm men migration neoplastic cell novel novel strategies oncoprotein p21 preclinical efficacy protein expression public health relevance receptor receptor binding release of sequestered calcium ion into cytoplasm research study small molecule tool tumor tumor growth tumor progression tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Breast cancer (BrCa) ranks second in both incidence and cancer deaths for women in the USA. The heterogenous nature of BrCa intensifies its complexity implying that mechanisms change during cancer progression so that certain proteins may step in to support proliferation. Recent advances have revealed significant contributions of chemokines and their receptors in tumor growth, survival after chemotherapy, and organ-specific metastasis. CXCR7 is the latest CXC-chemokine receptor implicated in BrCa growth, although its mechanism of tumor growth enhancement remains unclear. CXCR7 can heterodimerize with CXCR4, bind to SDF-1 (CXCL12), and CXCL11. No direct ligand mediated physiological action has been implicated for CXCR7 in BrCa other than facilitating CXCR4-mediated activity, however, studies in other cancers have implicated CXCR7 in cell proliferation, anti-apoptotic activity and cell-cell adhesion. Our preliminary data shows enhanced but heterogeneous CXCR7 expression in primary breast cancer. More interestingly, CXCR7 is found to colocalize with epidermal growth factor receptor (EGFR), more pronounced in primary breast cancer tissues than normal breast tissue. In vitro experiments demonstrate a link between high CXCR7expression and proliferation in established BrCa cell lines, depletion of which causes cell cycle arrest and reduced activation of MAP kinases, such as ERK1/2. Based on these observations, it is hypothesized that CXCR7 trans-regulates EGFR by physical interaction that leads to enhanced tumor growth and potentially cancer progression. The goal of this project is to understand the mechanism by which CXCR7 modulates tumor cell growth in vitro and in vivo. It is proposed that CXCR7 is an important modulator of cell cycle progression and proliferation of CXCR7 expressing breast cancer cells. CXCR7 may play a critical role in conjunction with EGFR in breast cancer progression. To test these hypotheses, two specific aims are proposed: 1. Demonstrate the biologic consequence of altering the expression of CXCR7 with or without altering its co-receptor CXCR4 in a subset of breast cancer lines. Studies will include verifying that altering CXCR7 expression leads to changes in cell proliferation and other phenotypic changes using RNAi and forced gene expression strategies. 2. Elucidate the mechanism of breast cancer growth by CXCR7- EGFR interaction using both novel and classical techniques. Furthermore, the role of CXCR7 in vivo tumor growth promotion in human breast cancer models will be investigated, using CXCR7 and EGFR inhibitors and/or BrCa cells with stable CXCR7 depletion. This study will provide insight into the unique role of CXCR7 in BrCa and potentially provide a powerful tool for improved strategies to attack cancer. The project will also provide the young investigator thorough research training in breast cancer research and apply the basic mechanistic approach for assessing preclinical efficacy of antitumor therapies.

描述（由申请人提供）：乳腺癌（BRCA）在美国女性的发病率和癌症死亡中排名第二。 BRCA的异质性增强了其复杂性，这意味着机制在癌症进展过程中发生了变化，因此某些蛋白质可以介入以支持增殖。最近的进步揭示了趋化因子及其受体在肿瘤生长，化疗后的生存和器官特异性转移方面的显着贡献。 CXCR7是与BRCA生长有关的最新CXC-emokine受体，尽管其肿瘤生长的增强机制尚不清楚。 CXCR7可以与CXCR4，结合SDF-1（CXCL12）和CXCL11异二聚二聚体。除了促进CXCR4介导的活性以外，在BRCA中，没有直接配体介导的生理作用与CXCR7有关，但是，对其他癌症的研究与CXCR7有关，与细胞增殖，抗凋亡活性和细胞细胞粘附有关。我们的初步数据显示了原发性乳腺癌中增强但异质的CXCR7表达。更有趣的是，发现CXCR7与表皮生长因子受体（EGFR）共定位，在原发性乳腺癌组织中比正常乳腺组织更为明显。体外实验表明，在已建立的BRCA细胞系中，高CXCR7表达与增殖之间存在联系，这会导致细胞周期停滞和降低MAP激酶的激活，例如ERK1/2。基于这些观察结果，假设CXCR7通过物理相互作用来跨性EGFR，从而导致肿瘤生长增强并潜在癌症进展。该项目的目的是了解CXCR7在体外和体内调节肿瘤细胞生长的机制。有人提出，CXCR7是表达乳腺癌细胞的CXCR7的细胞周期进程和增殖的重要调节剂。 CXCR7在乳腺癌进展中可能与EGFR结合起关键作用。为了检验这些假设，提出了两个具体的目的：1。证明在乳腺癌系的子集中改变或不改变其共受体CXCR4而改变CXCR7的表达的生物学结果。研究将包括验证改变CXCR7表达会导致使用RNAi和强迫基因表达策略的细胞增殖和其他表型变化的变化。 2。使用新颖和经典技术来阐明CXCR7- EGFR相互作用的乳腺癌生长机理。此外，将研究CXCR7在人类乳腺癌模型中促进CXCR7的作用，使用CXCR7和EGFR抑制剂和/或BRCA细胞具有稳定的CXCR7消耗。这项研究将洞悉CXCR7在BRCA中的独特作用，并有可能为改善攻击癌症的策略提供强大的工具。该项目还将为乳腺癌研究的年轻研究者提供彻底的研究培训，并采用评估抗肿瘤疗法临床前疗效的基本机械方法。