权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Regulation of Rap1 Prenylation and Trafficking in Breast Cancer

乳腺癌中 Rap1 异戊二烯化和贩运的调控

基本信息

批准号：
9026584
负责人：
Carol Lucille Williams
金额：
$ 35.17万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9026584
关键词：
4T1 Adenosine A2B Receptor Adherens Junction Affect Agonist Animal Model Breast Cancer Cell Breast Cancer Patient Breast Cancer cell line Breast cancer metastasis C-terminal Cadherins Cell Nucleus Cell membrane Cell-Cell Adhesion Cells Clinic Clinical Clinical Trials Cyclic AMP-Dependent Protein Kinases Disease Drug Targeting Drug usage Endocytosis Event Exhibits FDA approved G-Protein-Coupled Receptors Goals Health Human Immunocompetent Immunodeficient Mouse MCF7 cell MDA MB 231 Malignant Neoplasms Mammary Gland Parenchyma Mammary Neoplasms Mediating Membrane Membrane Protein Traffic Metastatic breast cancer Modeling Molecular Chaperones Molecular Profiling Monomeric GTP-Binding Proteins Neoplasm Metastasis Nuclear Nuclear Translocation Outcome Pathway interactions Patients Pharmaceutical Preparations Phenotype Proteins RNA Interference Rattus Receptor Activation Regulation Reporting Research Signal Pathway Signal Transduction Staging Testing Tissue Microarray Tumor Subtype Xenograft procedure autocrine base beta catenin beta-adrenergic receptor dimethylbenzanthracene drug testing innovation interest isoprenoid malignant breast neoplasm malignant phenotype mutant neoplastic cell novel novel strategies novel therapeutic intervention paracrine prenylation receptor receptor expression receptor-mediated signaling trafficking tumor tumor microenvironment tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The proposed research will explore a new approach to diminish breast cancer metastasis by targeting G protein-coupled receptors (GPCRs) that control the prenylation of the small GTPase Rap1B. Prenylated Rap1B localizes at the plasma membrane of breast cancer cells and stabilizes adherens junctions, which promotes cell-cell adhesion and diminishes the release of metastatic cells from breast tumors. We recently discovered that Rap1B prenylation is suppressed by activating adenosine A2B receptors (A2BR) on breast cancer cells. We reported that A2BR activation causes protein kinase A to phosphorylate newly synthesized Rap1B, which decreases the interaction of Rap1B with the chaperone protein SmgGDS and prohibits Rap1B from entering the prenylation pathway. These events promote the cytosolic and nuclear accumulation of non-prenylated Rap1B, resulting in loss of cell-cell adhesion and acquisition of a metastatic phenotype. This GPCR-mediated pathway that promotes the metastatic phenotype is very novel, because it was previously thought that cells do not possess signaling mechanisms to suppress prenylation, and it was thought that suppressing the prenylation of small GTPases would inhibit, rather than promote, metastasis. Based on our discovery, inactivating A2BR should restore Rap1B prenylation and trafficking to the cell membrane, which will increase cell- cell adhesion and diminish the release of metastatic cells from the tumor. We recently discovered that other GPCRs (in addition to A2BR) can suppress Rap1B prenylation in breast cancer cells. These GPCRs are inactivated by drugs that are currently being given to patients with diseases other than cancer. We hypothesize that these drugs can be used to inactivate the GPCRs that suppress the prenylation of Rap1B in breast cancer cells, resulting in increased Rap1B prenylation, increased cell-cell adhesion, and diminished metastasis. This hypothesis will be tested by 1) identifying GPCRs that promote the metastatic phenotype of cultured breast cancer cells by suppressing the prenylation and membrane trafficking of Rap1B, 2) testing drugs that inactivate these GPCRs, to determine if they will diminish breast cancer metastasis in animal models by restoring normal Rap1B prenylation in the tumor cells, and 3) examining patients' breast tumors to determine if expression of specific GPCRs and diminished Rap1B prenylation are associated with specific tumor subtypes and a more aggressive stage. Accomplishing these goals will provide significant benefits by developing an innovative strategy to inhibit breast cancer metastasis.