c-Abl-mediated Suppression of Breast Cancer Development and Metastasis

c-Abl 介导的乳腺癌发展和转移抑制

• 批准号: 9246980
• 负责人: William Schiemann
• 金额: $ 32.83万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-14 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9246980
• 关键词: ABL1 gene; Address; Adhesions; Alpha Cell; Automobile Driving; Benign; Biomechanics; Breast Cancer Patient; Cancer Etiology; Cancer Patient; Cancer cell line; Cell Proliferation; Cell Survival; Cessation of life; Characteristics; Chinese Herbs; Clinical; Clinical Trials Design; Comprehensive Cancer Center; Coupled; Cyclophosphamide; Cytotoxic agent; Data; Development; Disease; Doxorubicin; ERBB2 gene; Effectiveness; Epithelial; Estrogens; Event; Evolution; Exhibits; Extracellular Matrix; FDA approved; Failure; Family member; Fatty acid glycerol esters; Focal Adhesions; Hormonal; Hormone Receptor; Human; Imatinib; Implant; In Vitro; In complete remission; Individual; Integrins; Knowledge; Large Intestine Carcinoma; Lead; Malignant Epithelial Cell; Malignant Neoplasms; Mammary Gland Parenchyma; Mammary gland; Matrix Metalloproteinases; Measures; Mediating; Mediator of activation protein; Medicine; Mesenchymal; Metastatic breast cancer; Modeling; Molecular; Monitor; Mus; Natural Products; Neoplasm Metastasis; Oncogenic; Outcome; Partner in relationship; Pathologic; Pathway interactions; Phase III Clinical Trials; Phenotype; Pre-Clinical Model; Progesterone; Property; Protein Tyrosine Kinase; Proteins; Randomized; Recurrence; Relapse; Retrospective Studies; Role; Sampling; Science; Signal Transduction; Specimen; Survival Rate; TP53 gene; Therapeutic Effect; Tissue Microarray; Tissues; Tumor Initiators; Tumor Subtype; Tumor Suppression; Tumor Suppressor Proteins; Tumorigenicity; United States; Woman; base; c-abl Proto-Oncogenes; cancer subtypes; chemotherapy; cohort; cytotoxic; docetaxel; in vivo; in vivo Model; innovation; insight; killings; malignant breast neoplasm; mechanotransduction; member; migration; mouse model; mutant; novel; novel marker; outcome forecast; pre-clinical; predictive marker; programs; promoter; public health relevance; response; senescence; small molecule; standard of care; targeted treatment; therapeutic effectiveness; triple-negative invasive breast carcinoma; tumor; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): 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, those classified as being triple-negative breast cancers (TNBCs) are clinically unique via their presentation of aggressive and metastatic phenotypes, and their high propensity to recur rapidly following conventional chemotherapy treatment. TNBCs are also noteworthy by their failure to express hormone receptors (estrogen and progesterone) and ErbB2/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 and alleviating this aggressive breast cancer subtype. c-Abl is a ubiquitously expressed nonreceptor protein tyrosine kinase that governs cell proliferation, migration, and adhesion, as well as that of cell survival. Additionally, c-Abl can function as a suppressor or promoter of tumorigenesis in a cell- and context-specific manner. Importantly, we showed that the enforced expression of a constitutively-active c-Abl mutant (CST-Abl) alleviated TNBC development and metastasis in mice, doing so by inducing TNBCs to undergo mesenchymal-epithelial transition programs coupled to elevated p21 expression, and to diminished expression of matrix metalloproteinases. Along these lines, we recently observed TNBC tumorigenicity to be inversely related to c-Abl expression levels, which also predicts for TNBC response to docetaxel. Likewise, we discovered that the ancient Chinese herb Securinine exhibits potent cytotoxic activity against TNBCs propagated in 3D-organotypic cultures. Based on these and other preliminary findings, we hypothesize that measures capable of promoting c-Abl expression and activation will alleviate TNBC development and metastatic progression. These hypotheses will be addressed by four Specific Aims. Aim 1 will determine the role for oncogenic TGF-� signaling and mechanotransduction to inactivate the tumor suppressing functions of c-Abl in TNBCs. We will manipulate, both positively and negatively, the expression of �1 and �3 integrins and their effectors to gauge their function in driving c-Abl inactivation during specific stages of TNBC development and metastatic progression. Likewise, the validity of these molecular changes will be assessed using a human breast tissue microarray. Aim 2 will determine the role for p53 members in mediating tumor suppression by c-Abl in TNBCs, and in other non-TNBC subtypes. Additionally, the effectiveness of a novel allosteric c-Abl activator, DPH, to eradicate TNBCs will be assessed using in vitro and in vivo models of TNBC tumor development. Aim 3 will determine the value of c-Abl to predict TNBC response to docetaxel. We will manipulate c-Abl expression in human and murine TNBC cell lines, whose survival following docetaxel treatment will be assessed both in vitro and in vivo. Likewise, we will perform a retrospective study on annotated clinical specimens to validate c-Abl expression as a predictive biomarker for TNBC response to docetaxel. Lastly, Aim 4 will determine the therapeutic effectiveness of Securinine to eradicate TNBCs. Here we will manipulate the expression of c-Abl and p53 family members in late-stage TNBCs, whose survival when treated with Securinine, docetaxel, and TNBC standard-of-care agents will be determined and compared. Collectively, the findings obtained in this innovation application will provide novel molecular insights into how c-Abl suppresses TNBC tumorigenicity; they will also generate innovative translational outcomes in the form of novel biomarkers (e.g., c-Abl for docetaxel response) and treatment options (e.g., Securinine and DPH) for TNBCs.

描述（由申请人提供）：乳腺癌是一种异质性疾病，由至少 5 种主要肿瘤亚型组成，它们共同成为美国女性癌症死亡的第二大原因。在各个乳腺癌亚型中，被归类为三阴性乳腺癌 (TNBC) 的亚型在临床上是独一无二的，因为它们表现出侵袭性和转移性表型，并且在常规化疗治疗后极易迅速复发。 TNBC 还值得注意的是，它们无法表达激素受体（雌激素和孕激素）和 ErbB2/HER2，这种表型导致靶向化疗（例如激素或 HER2 导向）无效，并导致 TNBC 患者预后不良。尽管近年来我们对 TNBC 的分子特征和临床表现的了解有所增加，但科学和医学仍然缺乏对 TNBC 发展和转移的足够了解，无法合成能够特异性靶向和减轻这种侵袭性乳腺癌亚型的化疗药物。 c-Abl 是一种普遍表达的非受体蛋白酪氨酸激酶，控制细胞增殖、迁移和粘附以及细胞存活。此外，c-Abl 可以以细胞和环境特异性的方式充当肿瘤发生的抑制子或促进子。重要的是，我们发现，组成型活性 c-Abl 突变体 (CST-Abl) 的强制表达通过诱导 TNBC 经历间充质-上皮转化程序，并与 p21 表达升高和基质金属蛋白酶表达减少相结合，从而减轻了小鼠 TNBC 的发展和转移。沿着这些思路，我们最近观察到 TNBC 致瘤性与 c-Abl 表达水平呈负相关，这也预测了 TNBC 对多西紫杉醇的反应。同样，我们发现古老的中药叶秋碱对在 3D 器官型培养物中繁殖的 TNBC 表现出强大的细胞毒活性。基于这些和其他初步发现，我们假设能够促进 c-Abl 表达和激活的措施将减轻 TNBC 的发展和转移进展。这些假设将通过四个具体目标来解决。目标 1 将确定致癌 TGF-β 信号传导和机械转导在 TNBC 中灭活 c-Abl 肿瘤抑制功能的作用。我们将积极和消极地操纵α1和β3整合素及其效应子的表达，以测量它们在TNBC发展和转移进展的特定阶段驱动c-Abl失活的功能。同样，这些分子变化的有效性将使用人类乳腺组织微阵列进行评估。目标 2 将确定 p53 成员在 TNBC 和其他非 TNBC 亚型中通过 c-Abl 介导肿瘤抑制中的作用。此外，将使用 TNBC 肿瘤发展的体外和体内模型来评估新型变构 c-Abl 激活剂 DPH 根除 TNBC 的有效性。目标 3 将确定 c-Abl 的值来预测 TNBC 对多西他赛的反应。我们将操纵人和鼠 TNBC 细胞系中的 c-Abl 表达，将在体外和体内评估多西紫杉醇治疗后细胞的存活率。同样，我们将对带注释的临床标本进行回顾性研究，以验证 c-Abl 表达作为 TNBC 对多西紫杉醇反应的预测生物标志物。最后，目标 4 将确定 Securinine 根除 TNBC 的治疗效果。在这里，我们将操纵晚期 TNBC 中 c-Abl 和 p53 家族成员的表达，将确定并比较使用 Securinine、多西紫杉醇和 TNBC 标准护理药物治疗时的存活率。总的来说，这项创新应用中获得的发现将为 c-Abl 如何抑制 TNBC 致瘤性提供新的分子见解；他们还将以新型生物标志物（例如用于多西紫杉醇反应的 c-Abl）和 TNBC 的治疗方案（例如 Securinine 和 DPH）的形式产生创新的转化结果。