Role of WAVE3 in the Development and Progression of Breast Cancer

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 是美国女性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(TNBCs)是临床上独一无二的侵袭性表现。 表型，以及在常规化疗后迅速复发的高倾向。TNBCs做到了 不表达激素受体(雌激素和孕激素)和HER2，这是一种使靶向 化疗(如激素或HER2)无效，并导致TNBC预后不良。 病人。尽管我们对TNBCs的分子特征和临床表现的了解 虽然近年来有所增加，但科学和医学仍然缺乏对TNBC发展的足够了解和 转移允许合成能够专门针对这种侵袭性乳房的化疗药物 癌症亚型。Wave3(W3)是WASP/WAVE肌动蛋白结合蛋白家族中的一员，在肌动蛋白中发挥重要作用 在调控细胞形态、肌动蛋白聚合和细胞骨架重塑以及细胞中的重要作用 运动性和侵犯性。重要的是，我们发现W3在TNBCs中的表达异常升高，并且 W3的强制表达促进了TNBCs侵袭性和转移性表型的获得。基座 根据这些和其他初步发现，我们假设(I)c-Abl介导的WAVE3的磷酸化 促进晚期TNBCs的侵略性；(Ii)WAVE3和YBox1(YB1)之间的相互作用，a 肿瘤干细胞特异性转录因子，促进TNBC肿瘤的发生和发展； (Iii)W3表达的细胞缺失使TNBCs对标准的抗癌和凋亡活性敏感。 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磷酸化在TNBC发生发展中的作用。我们将创建c-Abl- 并确定它们在体外和体内调节TNBC致瘤性的能力。 同样，质谱分析发现了新的WAVE3结合蛋白，如YB1。目标2将 探讨W3/YB1相互作用在促进肿瘤发育和转移中的意义 TNBCs的进展，以及在癌症干细胞转录机制的调节中，这将是 在体外和体内TNBCs模型中测定。Aim 3将使用我们新开发的ECO纳米颗粒来 特异性地将W3抑制剂输送到TNBC肿瘤，并确定W3灭活对 恢复/提高TNBCs对化疗的敏感性，以此作为减缓TNBC进展和 转移。总的来说，在这一创新应用中获得的发现将提供新的分子 关于W3如何促进TNBC致瘤性的见解。它们还将产生创新的翻译成果 以使用W3抑制剂使TNBCs对标准护理重新敏感的新治疗选项的形式 化疗和减缓TNBC的发展和转移进展。

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.