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: 7841847
• 负责人: PARTHA ROY
• 金额: $ 24.89万
• 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 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7841847
• 关键词: Actin-Binding Protein; Actins; Amino Acid Motifs; Animal Model; Binding; Biochemical; Breast Cancer Cell; Breast Carcinoma; Cell-Matrix Junction; Cells; Cellular Structures; Characteristics; Complex; Cytoskeleton; Data; Disease; Disseminated Malignant Neoplasm; Distant; Dominant-Negative Mutation; Down-Regulation; E-Cadherin; Epithelial Cells; Family; Fluorescence Resonance Energy Transfer; G Actin; Gene Silencing; Generations; Goals; Growth; Human; In Vitro; Individual; Intercellular Junctions; Intervention; 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; Proteins; Recruitment Activity; Regulation; Research; Research Personnel; Role; Series; Side; Signal Pathway; Signal Transduction; Stimulus; Structure; System; Techniques; Testing; Therapeutic; Time; Translating; Tumor Cell Invasion; Tumor Suppressor Proteins; Wiskott-Aldrich Syndrome; base; cell growth; cell motility; cell type; design; in vivo; infiltrating duct carcinoma; insight; malignant breast neoplasm; migration; monomer; mortality; mutant; neoplastic cell; overexpression; polymerization; profilin; programs; response; spatiotemporal; tumor; tumorigenesis; vasodilator-stimulated phosphoprotein

DESCRIPTION (provided by applicant): 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's mutants 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 constructs to 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 cancer metastasis.

描述(申请人提供)：乳腺癌的死亡是由于远处器官的转移，很大程度上是由于侵袭性的增加。以前的研究表明，在转移性乳腺癌细胞中，Profilin(一种肌动蛋白结合蛋白，也具有肿瘤抑制作用)的表达下调。这一点，加上我们的初步数据显示，过度表达Profilin或其选择性地与肌动蛋白或富含Pro基序(PRM)蛋白结合受损的突变体显著减少了乳腺癌细胞的迁移，导致了Profilin功能调节乳腺癌侵袭和转移的假设(假设)。该项目的总体目标是确定如何利用Profilin的扰动来抑制乳腺癌的侵袭和转移。为了验证这一假设，在目标I中，我们将首先使用一系列分子结构来确定Profilin功能的调节如何改变乳腺癌细胞的迁移。接下来，为了确定Profilin依赖的细胞迁移变化的分子基础，我们将研究Profilin的各种扰动如何改变细胞的细胞骨架结构和突起能力。在AIM II中，我们将首先使用光诱导技术来确定Profilin在迁移细胞中的功能是否在空间上受到限制。接下来，我们将有选择地取消Profilin与不同类别的PRM蛋白的相互作用，以确定乳腺癌细胞迁移中的关键PRM相互作用，然后使用荧光共振能量转移(FRET)技术来研究这些相互作用在细胞迁移过程中的时空方面。在目标III中，我们将首先确定Profiin的扰动如何在部分模拟肿瘤细胞-间质相互作用的体外环境中改变乳腺癌细胞的侵袭。最后，使用动物模型，我们将测试Profilin的扰动是否在抑制乳腺癌转移方面有效。