Profilin as a target to suppress invasive breast cancer

Profilin 作为抑制浸润性乳腺癌的靶点

• 批准号: 7496231
• 负责人: PARTHA ROY
• 金额: $ 3.31万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-12 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7496231
• 关键词: Actin-Binding Protein; Actins; Amino Acid Motifs; Animal Model; Binding; Biochemical; Breast; Breast Cancer Cell; Breast Carcinoma; Cell-Matrix Junction; Cells; Cellular Structures; Characteristics; Class; Complex; Cytoskeleton; Data; Disease; Disseminated Malignant Neoplasm; Distant; Dominant-Negative Mutation; Down-Regulation; Ductal Carcinoma Cell; E-Cadherin; Epithelial Cells; Family; Fluorescence Resonance Energy Transfer; G Actin; Gene Silencing; Generations; Goals; Growth; Human; In Vitro; Individual; Intercellular Junctions; Intervention; Invasive; Knowledge; Lead; Link; Location; Malignant Epithelial Cell; Mammary gland; Metastatic to; Modeling; Molecular; Morphology; Neoplasm Metastasis; Neoplastic Cell Transformation; Organ; Play; Plus End of the Actin Filament; Process; Proline; Protein Overexpression; Proteins; Recruitment Activity; Regulation; Research; Research Personnel; Role; Series; Side; Signal Pathway; Signal Transduction; Stimulus; Structure; System; Techniques; Testing; Therapeutic; Thinking; Time; Translating; Tumor Cell Invasion; Tumor Suppressor Proteins; Wiskott-Aldrich Syndrome; base; cell growth; cell motility; cell type; design; ductal breast carcinoma; in vivo; insight; malignant breast neoplasm; migration; monomer; mortality; neoplastic cell; polymerization; profilin; programs; response; spatiotemporal; tumor; tumorigenesis; vasodilator-stimulated phosphoprotein

Breast cancer mortality is due to metastatic involvement of distant organs driven in large part by increased invasiveness. Previous studies show downregulation in the expression of profilin (an actin-binding protein which also has a tumor-suppressive effect) in metastatic breast cancer cells. This, taken together with our preliminary data showing that overexpressing profilin or it'smutants that are selectively impaired in binding to either actin or proline-rich motif (PRM) proteins significantly decreases the migration of breast carcinoma cells, leads to a hypothesis that profilin's function regulates breast cancer invasion and metastasis (HYPOTHESIS). The overall goal of the project is determine how perturbations of profilin can be utilized to suppress breast cancer invasion and metastasis. To test the hypothesis, in Aim I, we will first use a series of molecular constructsto determine how modulations of profilin's function alter the migration of breast cancer cells. Next, in order to determine the molecular basis for profilin-dependent changes in cell migration, we will investigate how various perturbations of profilin alter the cytoskeletal structure and the protrusive ability of cells. In Aim II, we will first employ photomanipulative techniques to determine whether profilin's function is spatially restricted in migrating cells. Next, we will abolish profilin's interaction selectively with different classes of PRM proteins to identify the key PRM interactions in breast cancer cell migration, and then use fluorescence resonance energy transfer (FRET) technique to study the spatiotemporal aspects of these interactions during cell migration. In Aim III,we will first determine how perturbations of profiin alter breast cancer cell invasion in an in vitro milieu partially mimicking tumor cell-stromal interactions. Finally, using animal model we will test whether perturbations of profilin are effective in inhibiting breast cancermetastasis.

乳腺癌的死亡率在很大程度上是由于远处器官的转移性累及所致