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

• 批准号: 10400050
• 负责人: KHALID SOSSEY-ALAOUI
• 金额: $ 40.7万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10400050
• 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; 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 of activation protein; Medicine; Metastatic breast cancer; Molecular; Morphology; Mus; Neoplasm Metastasis; Nuclear Translocation; Oncogenic; Organ; Outcome; Pathology; Pathway interactions; Patients; Phenotype; Phosphorylation; Phosphorylation Site; Phosphotransferases; Play; Primary Neoplasm; Progesterone; Prognosis; Proteins; Publishing; Reaction; Recurrence; Resistance; Role; Science; Series; Small Interfering RNA; Survival Rate; System; Testing; Time; Tissues; Transcriptional Regulation; Transforming Growth Factor beta; Tumor Subtype; Tumorigenicity; United States; Woman; aggressive breast cancer; anti-cancer; base; 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; 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

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.

乳腺癌是一种异质性疾病，由至少5种主要肿瘤亚型组成， 是美国女性癌症死亡的第二大原因。在个体乳腺癌中， 三阴性乳腺癌（TNBC）是临床上独特的，通过他们的侵略性表现， 表型，并且在常规化疗治疗后快速复发的高倾向。跨国公司确实 不表达激素受体（雌激素和孕酮）和HER 2，这是一种使靶向 化学疗法（例如，激素或HER 2导向）无效，并导致TNBC的不良预后 患者尽管我们对TNBC的分子特征和临床表现的理解， 近年来，科学和医学仍然缺乏对TNBC发展的足够了解， 转移，以允许合成能够特异性靶向这种侵袭性乳腺癌的化学疗法 癌症亚型WAVE 3（W3）是肌动蛋白结合蛋白WASP/WAVE家族的成员，在肌动蛋白结合中起着重要的作用。 在控制细胞形状/形态、肌动蛋白聚合和细胞骨架重塑中起重要作用， 运动性和侵袭性。重要的是，我们发现W3表达在TNBC中异常升高， W3的强制表达促进了TNBC中侵袭性和转移性表型的获得。基于 基于这些和其他初步发现，我们假设（i）c-Abl介导的WAVE 3磷酸化 促进晚期TNBC的侵袭性;（ii）WAVE 3和YBox 1（YB 1）之间的相互作用， 癌症干细胞特异性转录因子，增强TNBC肿瘤的发展和进展;和 (iii)W3表达的细胞耗竭使TNBC对标准- 护理化疗。这些假设将通过三个具体目标来解决。目标1将决定 c-Abl介导的W3磷酸化对TNBC发展和进展的作用。我们将创造c-Abl- 在一些实施方案中，本发明涉及抗W3突变体，并确定它们在体外和体内调节TNBC致瘤性的能力。 同样，质谱分析鉴定了新的WAVE 3结合蛋白，如YB 1。目标2将 探讨W3/YB 1相互作用在促进肿瘤发生、转移中的意义 肿瘤干细胞的转录机制的调节，这将是 在TNBC的体外和体内模型中测定。Aim 3将使用我们新开发的ECO纳米颗粒， 特异性地将W3抑制剂递送至TNBC肿瘤，并确定W3失活的有效性， 恢复/增强TNBC对化疗的敏感性，作为缓解TNBC进展的手段， 转移总的来说，在这项创新应用中获得的发现将提供新的分子 深入了解W3如何促进TNBC致瘤性。它们还将产生创新的转化成果 以使用W3抑制剂使TNBC对标准治疗重新敏感的新型治疗选择的形式， 化疗和缓解TNBC发展和转移进展。