Inducible PTK6 expression drives oncogenic signaling in breast cancer

诱导性 PTK6 表达驱动乳腺癌中的致癌信号传导

• 批准号: 9148251
• 负责人: Carol A Lange
• 金额: $ 43.22万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-25 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9148251
• 关键词: Address; Adrenal Cortex Hormones; Advanced Malignant Neoplasm; Adverse effects; Agonist; Antibodies; Antineoplastic Agents; Behavior; Breast; Cancer Relapse; Cell Nucleus; Cell Surface Receptors; Cell Survival; Cell Therapy; Cell physiology; Cells; Cellular Stress; Cellular biology; Clinical; Complex; Data; Dependence; Development; Dexamethasone; Diagnosis; Disease; Drug Targeting; Drug resistance; Estrogen receptor negative; Family member; Gene Targeting; Genes; Glucocorticoid Receptor; Glucose; Goals; Growth; HIF1A gene; Health; Hormone Receptor; Hormones; Human; Hydrocortisone; Hypoxia; Hypoxia Inducible Factor; In Vitro; Inflammatory; Intestines; Knock-in Mouse; Lead; Ligands; Link; Luciferases; MAP Kinase Gene; MAPK7 gene; Malignant - descriptor; Malignant Neoplasms; Mammary Gland Parenchyma; Mammary Neoplasms; Mediating; Mediator of activation protein; Metastatic breast cancer; Modeling; Mus; Neoplasm Metastasis; Nuclear; Oncogenic; Outcome; Oxidative Stress; Oxygen; Pathway interactions; Patients; Phenotype; Phosphorylation; Phosphotransferases; Process; Protein Kinase; Protein Tyrosine Kinase; Receptor Protein-Tyrosine Kinases; Recurrent disease; Resistance; Risk; Role; Signal Pathway; Signal Transduction; Stress; Stress-Induced Protein; Testing; Transgenes; Treatment Efficacy; Xenograft Model; biological adaptation to stress; cancer cell; cell motility; chemotherapy; effective therapy; feeding; hypoxia inducible factor 1; improved; in vivo; inhibitor/antagonist; knock-down; malignant breast neoplasm; migration; mitogen-activated protein kinase p38; neoplastic cell; novel; outcome forecast; p38 MAPK Signaling Pathway; prevent; response; scaffold; therapy development; therapy resistant; transcription factor; triple-negative invasive breast carcinoma; tumor; tumor progression

 DESCRIPTION (provided by applicant): Thirty percent of patients diagnosed with breast cancer ultimately develop metastatic disease and relapse in a process that can take years to decades. Tumor progression in the face of initially effective treatment represents a major clinical challenge. Tumor cells circumvent treatment via activation of adaptive and stress-induced signaling pathways. Metastasis and drug resistance occur in response to activation of a variety of stress-sensing signaling pathways whose cellular functions are orchestrated by the oxygen- responsive hypoxia inducible factors (HIFs). Yet, directly targeting HIFs is challenging as they are localized to the nucleus and regulate hundreds of genes. Most "HIF inhibitors" act indirectly rather than directly on HIFα stability/activity. To improve efficacy of treatments for breast cancr patients at risk of developing metastatic disease, "driver" genes acting downstream of HIFs must be identified and targeted. We have identified protein tyrosine kinase 6 (PTK6) as a major driver of oncogenic signaling in breast cancer. PTK6, also known as breast tumor kinase (Brk) is a non-receptor tyrosine kinase that is expressed in up to 86% of breast cancers but is very low or absent from normal breast tissues. Notably, increased PTK6 expression predicts poor outcome and mediates resistance to anti-cancer agents (ex. antibodies) aimed at cell-surface receptors. Forced expression of PTK6 confers "hallmarks" of cancer in vitro, including increased proliferation, pro-survival and migration. Recently, we found that PTK6 is rapidly upregulated in response to conditions that increase cellular stress and facilitate tumor progression, such as oxidative stress, low glucose, UV, and hypoxia. Robust PTK6 expression is also induced by corticosteroids, intracellular ligands for nuclear glucocorticoid receptors (GRs) and mediators of host stress responses. Notably, expression of GR is tightly associated with poor outcome in basal-type or triple-negative (ER-/PR-/Her2-) breast cancer (TNBC). TNBC cells also constitutively express high levels of HIF1α and HIF2α, transcription factor mediators of cellular responses to stress. Our most recent preliminary data suggest that GR/HIF complexes induce PTK6 in response to a variety of cellular stresses that may include chemotherapy. Once expressed, PTK6 activates the stress-associated protein kinases, p38 MAPK and ERK5, two emerging effectors of survival, chemo-resistance, EMT, and migratory/invasive behavior in breast cancer. These data collectively support a model in which cortisol/GR and/or tumor-associated stress mediate HIF-induced PTK6 expression, which then turns on stress-activated signaling pathways (p38 MAPK and ERK5), leading to increased cancer cell survival and the acquisition of migratory/invasive behaviors. In short, we hypothesize that inducible PTK6 confers chemo-resistance and metastatic behavior to tumor cells in vivo. Herein, we propose to define the requirements for PTK6 induction (Aim 1) and signal transduction (Aim 2) and test the role of PTK6 as a mediator of metastasis development and therapy-resistance in vivo using patient-derived xenograft (PDX) models of TNBC (Aim 3).

 描述（由申请人提供）：30%的乳腺癌患者最终发展为转移性疾病，并在可能需要数年至数十年的过程中复发。在最初有效的治疗面前肿瘤进展代表了主要的临床 挑战.肿瘤细胞通过激活适应性和应激诱导的信号通路来规避治疗。转移和耐药性响应于多种应激感测信号传导途径的激活而发生，所述应激感测信号传导途径的细胞功能由氧响应性缺氧诱导因子（HIF）协调。然而，直接靶向HIF具有挑战性，因为它们定位于细胞核并调节数百个基因。大多数“HIF抑制剂”间接而非直接作用于HIFα稳定性/活性。为了提高乳腺癌患者发生转移性疾病风险的治疗效果，必须鉴定和靶向作用于HIF下游的“驱动”基因。我们已经确定蛋白酪氨酸激酶6（PTK 6）是乳腺癌致癌信号传导的主要驱动因素。PTK 6，也称为乳腺肿瘤激酶（Brk），是一种非受体酪氨酸激酶，在高达86%的乳腺癌中表达，但在正常乳腺组织中表达非常低或不存在。值得注意的是，增加的PTK 6表达预测不良结果并介导对抗癌剂的抗性（例如，抗体）针对细胞表面受体。PTK 6的强制表达在体外赋予癌症的“标志”，包括增加的增殖、促存活和迁移。最近，我们发现PTK 6在增加细胞应激和促进肿瘤进展的条件下迅速上调，如氧化应激，低葡萄糖，UV和缺氧。皮质类固醇、核糖皮质激素受体（GR）的细胞内配体和宿主应激反应的介质也诱导PTK 6的稳健表达。值得注意的是，GR的表达与基底型或三阴性（ER-/PR-/Her 2-）乳腺癌（TNBC）的不良结局密切相关。TNBC细胞还组成性表达高水平的HIF 1 α和HIF 2 α，它们是细胞凋亡的转录因子介导物。 对压力的反应。我们最新的初步数据表明，GR/HIF复合物诱导PTK 6响应于各种细胞应激，可能包括化疗。一旦表达，PTK 6激活应激相关蛋白激酶p38 MAPK和ERK 5，这是乳腺癌中生存、化疗耐药性、EMT和迁移/侵袭行为的两种新兴效应物。这些数据共同支持一个模型，其中皮质醇/GR和/或肿瘤相关应激介导HIF诱导的PTK 6表达，然后打开应激激活的信号通路（p38 MAPK和ERK 5），导致癌细胞存活率增加和迁移/侵袭行为的获得。简而言之，我们假设诱导型PTK 6在体内赋予肿瘤细胞化学抗性和转移行为。在本文中，我们提出定义PTK 6诱导（Aim 1）和信号转导（Aim 2）的要求，并使用TNBC的患者来源的异种移植物（PDX）模型在体内测试PTK 6作为转移发展和治疗抗性的介体的作用（Aim 3）。