Role of WAVE3 in the Development and Progression of Breast Cancer

WAVE3 在乳腺癌发生和进展中的作用

基本信息

批准号：
10615730
负责人：
KHALID SOSSEY-ALAOUI
金额：
$ 36.09万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10615730
关键词：
ABL1 gene Actin-Binding Protein Actins Address Apoptosis Apoptotic Automobile Driving Binding Proteins Blood Brain Breast Cancer Patient Breast Cancer cell line Breast cancer metastasis Cancer Etiology Cell Nucleus Cell Shape Cells Cessation of life Clinical Complex Coupled Cytoplasm Cytoskeleton Development Disease Distant ERBB2 gene Estrogen Receptor alpha Estrogens Event Exhibits Exposure to Extracellular Matrix Degradation FDA approved Family Gene Expression Genetic Genetic Transcription Hormonal Hormone Receptor Human In Vitro Individual Induction of Apoptosis Invaded Knowledge Lymphatic System Maintenance Mass Spectrum Analysis Matrix Metalloproteinases Measures Mediating Mediator Medicine Metastatic breast cancer Molecular Morphology Mus Neoplasm Metastasis Nuclear Translocation Oncogenic Organ Outcome Pathology Pathway interactions Patients Phenotype Phosphorylation Phosphorylation Site Phosphotransferases Play Polymers Primary Neoplasm Progesterone Prognosis Proteins Publishing Reaction Recurrence Resistance Role Science Series Small Interfering RNA Subcategory Survival Rate System Testing Time Tissues Transcriptional Regulation Transforming Growth Factor beta Tumor Subtype Tumorigenicity United States Visual Woman aggressive breast cancer anti-cancer breast cancer progression cancer cell cancer stem cell cancer subtypes cell motility chemotherapy driving force effectiveness evaluation in vivo in vivo Model inhibitor innovation insight interest malignant breast neoplasm member migration mouse model mutant nanoparticle novel polymerization promoter protein activation response standard of care stem cell biology stem cell population targeted treatment transcription factor triple-negative invasive breast carcinoma tumor tumor progression

项目摘要

Breast cancer is a heterogeneous disease comprised of at least 5 major tumor subtypes that coalesce as the 2nd leading cause of cancer death in women in the United States. Amongst individual breast cancer subtypes, triple-negative breast cancers (TNBCs) are clinically unique via their presentation of aggressive phenotypes, and high propensity to recur rapidly following conventional chemotherapy treatment. TNBCs do not express hormone receptors (estrogen and progesterone) and HER2, a phenotype that renders targeted chemotherapies (e.g., hormonal or HER2-directed) ineffective and contributes to the poor prognosis of TNBC patients. Although our understanding of the molecular features and clinical manifestations of TNBCs has increased in recent years, science and medicine still lack sufficient knowledge of TNBC development and metastasis to permit the synthesis of chemotherapies capable of specifically targeting this aggressive breast cancer subtype. WAVE3 (W3) is a member of the WASP/WAVE family of actin-binding proteins and plays an essential role in governing cell shape/morphology, actin polymerization and cytoskeleton remodeling, and cell motility and invasion. Importantly, we showed that W3 expression is aberrantly elevated in TNBCs, and that enforced expression of W3 promotes the acquisition of invasive, and metastatic phenotypes in TNBCs. Based on these and other preliminary findings, we hypothesize that (i) c-Abl-mediated phosphorylation of WAVE3 promotes the aggressiveness of late-stage TNBCs; (ii) Interaction between WAVE3 and YBox1 (YB1), a cancer stem cell-specific transcription factor, enhances the development and progression of TNBC tumors; and (iii) cellular depletion of W3 expression sensitizes TNBCs to the anticancer and apoptotic activities of standard- of-care chemotherapies. These hypotheses will be addressed by three Specific Aims. Aim 1 will determine the role of c-Abl-mediated phosphorylation of W3 on TNBC development and progression. We will create c-Abl- resistant W3 mutants and determine their ability to regulate TNBC tumorigenicity both in vitro and in vivo. Likewise, mass-spectrometry analyses identified novel WAVE3-binding proteins, such as YB1. Aim 2 will investigate the significance of the W3/YB1 interaction in promoting the development and metastatic progression of TNBCs, and in the regulation of the transcription machinery of cancer stem cells, which will be determined in in vitro and in vivo models of TNBCs. Aim 3 will use our newly developed ECO nanoparticles to specifically deliver W3 inhibitors to TNBC tumors and determine the effectiveness of W3 inactivation to restore/enhance the sensitivity of TNBCs to chemotherapy as a means to alleviate TNBC progression and metastasis. Collectively, the findings obtained in this innovation application will provide novel molecular insights into how W3 promotes TNBC tumorigenicity. They will also generate innovative translational outcomes in the form of novel treatment options using W3 inhibitors to resensitize TNBCs to standard-of-care chemotherapies and to alleviate TNBC development and metastatic progression.

乳腺癌是一种由至少5种主要肿瘤亚型组成的异质性疾病，它们合并为美国妇女癌症死亡的第二大原因。在个体乳腺癌中亚型，三阴性乳腺癌（TNBC）在临床上通过侵略性而在临床上是独一无二的常规化学疗法治疗后，表型和迅速复发的倾向很高。 TNBC会这样做非表达激素受体（雌激素和孕激素）和HER2，这种表型的表型将其靶向化学疗法（例如激素或HER2指导）无效，并导致TNBC的预后不良患者。尽管我们对TNBC的分子特征和临床表现的理解具有近年来，科学和医学仍然缺乏对TNBC发展和转移允许合成能够特异性靶向这种侵略性乳房的化学疗法癌症亚型。 Wave3（W3）是肌动蛋白结合蛋白的WASP/WAVE家族的成员，并且播放在控制细胞形状/形态，肌动蛋白聚合和细胞骨架重塑和细胞中的重要作用运动和入侵。重要的是，我们表明W3表达在TNBC中异常升高，并且 W3的强制表达促进了TNBC中的侵入性和转移表型的获取。基于在这些和其他初步发现上，我们假设（i）c- abl介导的波3的磷酸化促进后期TNBC的侵略性；（ii）wave3和ybox1（yb1）之间的相互作用，a 癌症干细胞特异性转录因子增强了TNBC肿瘤的发育和进展。和（iii）W3表达的细胞耗竭使TNBC敏感到标准的抗癌和凋亡活性治疗化学疗法。这些假设将由三个特定目标解决。 AIM 1将确定 C-ABL介导的W3磷酸化在TNBC发育和进展中的作用。我们将创建C-ABL- 抗性W3突变体，并确定其在体外和体内调节TNBC肿瘤性的能力。同样，质谱分析鉴定出了新型的Wave3结合蛋白，例如YB1。目标2将研究W3/YB1相互作用在促进发展和转移方面的重要性在癌症干细胞的转录机制的调节中，TNBC的进展将是在TNBC的体外和体内模型中确定。 AIM 3将使用我们新开发的生态纳米颗粒来特异性地将W3抑制剂传递到TNBC肿瘤，并确定W3失活的有效性恢复/增强TNBC对化学疗法的敏感性，以减轻TNBC进展和转移。总的来说，在本创新应用中获得的发现将提供新的分子了解W3如何促进TNBC肿瘤性。他们还将产生创新的翻译成果使用W3抑制剂的新型治疗选择的形式，将TNBC归因于护理标准化学疗法并减轻TNBC的发展和转移进展。

项目成果

期刊论文数量（17）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

YB1 Is a Major Contributor to Health Disparities in Triple Negative Breast Cancer.

DOI：
10.3390/cancers13246262
发表时间：
2021-12-14
期刊：
Cancers
影响因子：
5.2
作者：
Rana PS;Wang W;Alkrekshi A;Markovic V;Khiyami A;Chan R;Perzynski A;Joseph N;Sossey-Alaoui K
通讯作者：
Sossey-Alaoui K

The WAVE2/miR-29/Integrin-β1 Oncogenic Signaling Axis Promotes Tumor Growth and Metastasis in Triple-negative Breast Cancer.

DOI：
10.1158/2767-9764.crc-22-0249
发表时间：
2023-01
期刊：
CANCER RESEARCH COMMUNICATIONS
影响因子：
0
作者：
Rana, Priyanka S.;Wang, Wei;Markovic, Vesna;Szpendyk, Justin;Chan, Ernest Ricky;Sossey-Alaoui, Khalid
通讯作者：
Sossey-Alaoui, Khalid

Targeted Deletion of Kindlin-2 in Mouse Mammary Glands Inhibits Tumor Growth, Invasion, and Metastasis Downstream of a TGF-β/EGF Oncogenic Signaling Pathway.

DOI：
10.3390/cancers14030639
发表时间：
2022-01-27
期刊：
Cancers
影响因子：
5.2
作者：
Wang W;Rana PS;Alkrekshi A;Bialkowska K;Markovic V;Schiemann WP;Plow EF;Pluskota E;Sossey-Alaoui K
通讯作者：
Sossey-Alaoui K

Role of Kindlin-2 in cancer progression and metastasis.