Novel Role of ThPOK in Mammary Carcinoma

ThPOK 在乳腺癌中的新作用

基本信息

批准号：
10595566
负责人：
Dietmar J Kappes
金额：
$ 62.27万
依托单位：
RESEARCH INST OF FOX CHASE CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-03 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10595566
关键词：
Alleles Animal Model Binding Binding Sites Biological Breast Cancer Cell Breast Cancer Patient Breast Cancer cell line Breast Carcinoma Cancer Biology Cancer Patient Cell Line Cells Cessation of life Classification Clinical Cytoplasm Cytoplasmic Tail Data Development Disease EGFR gene ERBB2 gene Epidermal Growth Factor Receptor Event Exhibits Family history of Family member Frameshift Mutation Frequencies Gene Expression Profile Genetic Genetic Transcription Health Hereditary Breast Carcinoma Human Incidence Link Maintenance Malignant Neoplasms Malignant neoplasm of ovary Mammary Neoplasms Mediating Molecular Mus Mutation Nuclear Outcome Patients Penetrance Probability Prognosis Prognostic Marker Proline Proteins Proteomics Recycling Refractory Research Resistance Role Signal Transduction Signaling Protein Surface Survival Analysis Testing Therapeutic Intervention Trastuzumab Treatment Failure Treatment outcome Variant Woman biochemical tools cancer initiation cancer predisposition cancer subtypes chemotherapy cohort enhancing factor improved innovation mRNA Differential Displays malignant breast neoplasm mortality mouse model novel novel therapeutic intervention predictive marker prevent prognostic tool prognostic value targeted treatment trafficking transcription factor tumor tumorigenesis

项目摘要

PROJECT SUMMARY/ABSTRACT Overview: There is an urgent need to understand the molecular basis of HER2+ breast cancer, given that the majority of patients eventually become refractory to treatment including with anti-HER2 therapy. Herein, we provide preliminary data linking poor clinical outcome of human HER2+ breast cancers with the presence of high cytoplasmic levels of the transcription factor ThPOK (cytoThPOK). Further, using a novel mouse model of cytoplasmically restricted ThPOK (ThPOKΔNLS mice), we establish a causal relationship between cytoThPOK and development of highly penetrant Her2+ breast cancer. Proteomic analysis of mouse breast cancer cells indicates that cytoThPOK interacts with multiple cytosolic proteins implicated in Her2 signaling, including several SH3 proteins that probably bind to a conserved proline-rich motif in ThPOK. Given the central role of HER2 signaling in HER2+ breast cancer biology, we hypothesize that cytoThPOK interaction with these factors enhances HER2-mediated signaling in some way, and that this represents an important driver of breast cancer development/progression, that has so far been overlooked. Research Focus: POK transcription factors have been implicated in diverse human cancers, which was presumed to reflect direct effects on transcription. In contrast, we now implicate cytosolic localization of ThPOK in breast cancer in humans and mice, demonstrating a novel mode of POK-mediated oncogenesis not based on nuclear function. These findings provide an innovative and compelling premise for the proposed studies. Specific Aims: We will elucidate the role of cytoThPOK in breast cancer according to 3 aims: SA-1: Elucidating molecular basis of ThPOKΔNLS–mediated oncogenesis - to test effect of cytoThPOK on HER2/EGFR expression and signaling in cell lines, and test the requirement for the ThPOK SH3-interaction domain for cytoThPOK-mediated breast cancer in mice. SA-2: Dissecting prognostic value and molecular basis for cytoplasmic localization of ThPOK in human BC - to evaluate correlation between high cytoThPOK and survival in different human HER2+ breast cancer subtypes, and determine the molecular basis for cytoplasmic localization of ThPOK in human breast cancer cells. SA-3: Elucidating effect of cytoThPOK on BC tumor maintenance - to elucidate whether cytoThPOK is required for tumor maintenance/progression of established cancers from ThPOKΔNLS mice, and characterize a new humanized ThPOK mouse model that expresses a variant hThPOKp.H22pTfs*6 allele found in some human breast cancer patients. Impact: Given the high incidence of cancer observed in mice with enforced cytoplasmic ThPOK localization and the high frequency of cytoplasmic ThPOK localization in human HER2+ breast cancer patients, elucidating the molecular basis by which cytoThPOK promotes breast cancer is likely to have high impact on human health. Here we combine novel animal models and molecular approaches to elucidate these mechanisms. These studies have the capacity to shift the basic conceptual framework by which POK factors are presumed to promote oncogenesis. Potentially, elucidating these mechanisms may lead to novel therapeutic approaches to target HER2+ breast cancer and other human malignancies in which cytoThPOK may be implicated.

项目摘要/摘要概述：考虑到您，迫切需要了解HER2+乳腺癌的分子基础大多数患者最终会对治疗（包括抗HER2治疗）的治疗难治性。提供初步数据，将人类HER2+乳腺癌的临床不良结局联系起来转录因子Thpok的高细胞质水平进一步使用新型小鼠模型细胞质限制了THPOK（THPOKΔNLS小鼠），我们在细胞to骨之间建立了因果关系以及高度渗透性HER2+乳腺癌的发展。表明细胞托普克与与HER2信号有关的多种胞质蛋白相互作用，包括几种可能结合了THPOK中富含脯氨酸的基序的SH3蛋白。 HER2信号传导在HER2+乳腺癌生物学中，我们假设细胞皮克与这些因素的相互作用以某种方式增强HER2介导的信号传导，这代表了乳腺癌的重要驱动力开发/进步，到目前为止被忽略了。研究重点：POK转录因素与多样化的人类癌症有关主题反映了对转录的直接影响。在人类和小鼠的乳腺癌中，证明了一种新型的改变的肿瘤发生关于核功能，这些发现为拟议的研究提供了令人信服和引人注目的前提。具体目的：根据3个目标：SA-1：我们将阐明细胞皮克在乳腺癌中的作用阐明thpokΔnls的分子基础 - 介导的肿瘤发生 - 测试细胞po的作用 HER2/EGFR表达和在细胞系中的信号传导，并测试线程3相互作用的需求 SA-2的细胞杆菌介导的乳腺癌的结构域：剖析计划和分子在人类BC中ThPOK的细胞质定位的基础 - 评估高高之间的相关性在不同的人类HER2+乳腺癌亚型中的细胞增生和存活，并确定分子基础用于人类乳腺癌细胞中THPOK的细胞质定位。在BC肿瘤维护上 - 阐明肿瘤维持/进展是否需要细胞杆菌来自ThpokΔnls小鼠已建立的癌症的癌症，并表征了一种新的人源化thosit小鼠模型在某些人类乳腺癌患者中发现了一种变异的HTPOKP.H22PTFS*6等位基因。影响：鉴于在具有强化细胞质THPOK定位的小鼠中观察到的癌症发生率很高以及在人类HER2+乳腺癌中的细胞质THPOK定位的高频，阐明细胞增生促进乳腺癌的分子基础可能对人类产生很大影响健康。我们结合了新型动物模型和分子方法来阐明这些机制这些研究具有推测POK因素的基本概念框架的能力为了促进肿瘤，阐明这些机制可能会导致新的治疗方法靶向HER2+乳腺癌和其他人类恶性肿瘤，其中可能涉及细胞增多症。