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

基本信息

批准号：
9762021
负责人：
Carol A Lange
金额：
$ 43.16万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-25 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9762021
关键词：
Address Adrenal Cortex Hormones Advanced Malignant Neoplasm Agonist Antibodies Antineoplastic Agents Behavior Breast Breast Cancer Prevention 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 Family member Genes Genetic Transcription Glucocorticoid Receptor Glucose Goals Growth Factor HIF1A gene Hormone Receptor Hormones Human Hydrocortisone Hypoxia Hypoxia Inducible Factor In Vitro Inflammatory Intestines Knock-in Mouse Lead Ligands Link Luciferases MAP Kinase Gene MAPK14 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 Relapse Resistance Risk Role Signal Pathway Signal Transduction Stress Stress-Induced Protein Testing Transgenes Treatment Efficacy Xenograft Model biological adaptation to stress breast cancer progression cancer cell cell motility chemotherapy effective therapy glucocorticoid receptor alpha hypoxia inducible factor 1 improved in vivo inhibitor/antagonist knock-down malignant breast neoplasm migration neoplastic cell novel outcome forecast protein expression public health relevance response scaffold side effect therapy resistant transcription factor triple-negative invasive breast carcinoma tumor tumor progression

项目摘要

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% 被诊断患有乳腺癌的患者最终会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，肿瘤进展代表了一个主要的临床问题。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是响应各种应激感应信号通路的激活而发生的，这些信号通路的细胞功能是由氧反应性缺氧诱导因子（HIF）协调的。然而，直接靶向 HIF 具有挑战性，因为它们位于细胞核并调节数百个基因，以间接而非直接作用于 HIFα 稳定性/活性，以提高乳腺癌治疗的功效。对于有转移性疾病风险的患者，必须识别并靶向作用于 HIF 下游的“驱动”基因。我们已确定蛋白酪氨酸激酶 6 (PTK6) 是乳腺癌（也称为乳腺肿瘤）致癌信号传导的主要驱动因素。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量非常低或不存在。值得注意的是，PTK6 表达增加预示着。 PTK6 的强制表达赋予癌症体外“标志”，包括增殖、促存活和迁移。 PTK6 会随着氧化应激、低葡萄糖、紫外线和缺氧等增加细胞应激和促进肿瘤进展的条件而迅速上调。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值得注意的是，GR 的表达与基底型或三阴性 (ER-/PR-/Her2-) 乳腺癌的不良预后密切相关。 TNBC）也组成性表达高水平的 HIF1α 和 HIF2α（细胞转录因子介质）。我们最新的初步数据表明，GR/HIF 复合物诱导 PTK6 响应多种细胞应激，其中可能包括化疗。一旦表达，PTK6 就会激活应激相关蛋白激酶 p38 MAPK 和 ERK5，这两种新兴效应器。这些数据共同支持了皮质醇/GR 和/或肿瘤相关应激介导 HIF 诱导的模型。 PTK6 表达，然后开启应激激活的信号通路（p38 MAPK 和 ERK5），导致癌细胞存活增加并获得迁移/侵袭行为。简而言之，我们利用诱导型 PTK6 赋予化疗耐药性和转移行为。在此，我们建议定义 PTK6 诱导（目标 1）和信号转导（目标 2）的要求，并测试 PTK6 的作用：使用 TNBC 患者来源的异种移植 (PDX) 模型，确定体内转移发展和治疗耐药性的介质（目标 3）。