Profilin as a target to suppress invasive breast cancer

Profilin 作为抑制浸润性乳腺癌的靶点

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：乳腺癌的死亡率是由于远处的器官的转移，很大程度上是由于增加的侵入性而引起的。先前的研究表明，在转移性乳腺癌细胞中，叶酸表达（肌动蛋白结合蛋白也具有肿瘤抑制作用）的表达下调。这与我们的初步数据一起，表明过度表达profilin或它的突变体在与肌动蛋白或富含脯氨酸的蛋白质（PRM）蛋白结合时被选择性损害可显着降低乳腺癌细胞的迁移，从而导致profilin的功能可调节乳腺癌的功能调节乳腺癌的癌症和转化（乳腺癌）。该项目的总体目标是确定如何利用叶酸的扰动来抑制乳腺癌的侵袭和转移。为了检验假设，在AIM I中，我们将首先使用一系列分子构建体来确定profilin功能的调节如何改变乳腺癌细胞的迁移。接下来，为了确定细胞迁移的分子依赖性变化的分子基础，我们将研究profilin的各种扰动如何改变细胞骨架结构和细胞的刺激能力。在AIM II中，我们将首先采用光手感技术来确定profilin的功能是否在迁移细胞中在空间上受到限制。接下来，我们将选择性地废除与不同类别的PRM蛋白的相互作用，以鉴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）技术来研究细胞迁移过程中这些相互作用的时空方面。在AIM III中，我们将首先确定profiin的扰动如何改变体外环境中部分模仿肿瘤细胞 - 基质相互作用。最后，使用动物模型，我们将测试profilin的扰动是否有效抑制乳腺癌转移。