SCAMP3 as a regulator of EGFR/STAT3 axis in triple-negative breast cancer

SCAMP3 作为三阴性乳腺癌 EGFR/STAT3 轴的调节因子

基本信息

批准号：
10643857
负责人：
Ivette Suarez
金额：
$ 12.61万
依托单位：
UNIVERSIDAD CENTRAL DEL CARIBE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10643857
关键词：
Address Biology Biomedical Research Breast Cancer Cell Breast Cancer Patient Breast Cancer Treatment Breast Epithelial Cells Cell Maintenance Cell Nucleus Cell Proliferation Cell model Cells Cessation of life Clinic Clinical Confocal Microscopy Cytometry DNA Binding Development Dimerization EGF gene ERBB2 gene Endocytosis Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Erlotinib Estrogens Future Genes Genetic Transcription Glioma Goals Green Fluorescent Proteins Heterogeneity Hormone Receptor Hormones Hypoxia In Vitro Incidence Invaded Investigation Janus kinase Knowledge Lesion MCF10A cells MDA-MB-468 Malignant Neoplasms Medicine Membrane Proteins Molecular Molecular Target Monitor Mus Neoplasm Metastasis Nuclear Translocation Pathogenesis Pathway interactions Patients Phosphorylation Primary carcinoma of the liver cells Productivity Progesterone Prognosis Proliferating Proteins Publishing Regulation Relapse Reporting Research Role SCID Mice Sampling Signal Pathway Signaling Protein Sorting Stat3 protein Survival Rate Testing Therapeutic Therapeutic Agents Time Tissues Translating Treatment Efficacy Visualization Work breast cancer progression cancer cell cancer stem cell endosome membrane erbB-2 Receptor experimental study improved inhibitor intravital imaging knock-down malignant breast neoplasm melanoma mortality novel novel therapeutics overexpression preclinical study prevent promoter receptor expression receptor mediated endocytosis receptor recycling response skills stem cell population stemness targeted treatment therapeutic target therapeutically effective trafficking transcriptome sequencing treatment strategy triple-negative invasive breast carcinoma tumor tumorigenesis vector control

项目摘要

Project Summary This proposal will investigate the molecular drivers that contribute to the progression of one of the most aggressive and metastatic types of breast cancer. Triple Negative Breast Cancer (TNBC) is characterized by the lack of hormone receptors (estrogen and progesterone) and HER2 expression and accounts for approximately 20% of all breast cancers. Due to its heterogeneity and dearth of defined specific molecular targets, TNBC treatment remains challenging. Accordingly, this study seeks to elucidate the molecular role of secretory carrier- associated membrane protein 3 (SCAMP3) on TNBC pathogenesis, with the goal of developing new therapies that will improve the survival rate of patients. Recently, SCAMP3 has been found overexpressed and associated with poor prognosis in hepatocellular carcinoma, melanoma, glioma, and breast cancer, suggesting that SCAMP3 has a key role in oncogenesis. However, the molecular mechanisms of how SCAMP3 promotes TNBC progression are poorly understood. SCAMP3 is a regulator of epidermal growth factor receptor (EGFR) trafficking within endosomal membranes promoting receptor recycling. EGFR mediated endocytosis is a mechanism of transport of cancer-associated signaling proteins, such as signal transducer and activator of transcription 3 (STAT3). EGFR and STAT3 have been associated with TNBC proliferation, invasion, metastasis, and cancer stem cell (CSC) maintenance. Our objectives are to determine the mechanisms by which SCAMP3 promotes TNBC progression and determine the interplay between SCAMP3/EGFR and STAT3 signaling pathways. We hypothesize that: 1) SCAMP3/EGFR mediated endocytosis regulates the activation of STAT3. 2) SCAMP3 signaling pathway promotes and maintains TNBC stemness via the modulation of EGFR/STAT3, and 3) SCAMP3 contributes to TNBC tumor formation and metastasis. To test these hypotheses, we propose the following aims: 1) To elucidate the mechanism of action of SCAMP3 on STAT3 activation; 2) Define the role of SCAMP3 in TNBC and CSCs regulation via STAT3 modulation: 2a) To elucidate the molecular mechanisms of SCAMP3 in CSCs maintenance in vitro; 2b) To investigate the effect of SCAMP3 in tumorigenesis and metastasis. We propose experiments that will monitor EGFR and STAT3 internalization, STAT3 DNA-binding activity, and transcriptional activity. We will identify the relevant driver genes that maintain cancer stemness in SCAMP3 overexpressing cells using RNAseq, which will be confirmed in patient samples. The studies have the potential to be rapidly translated to the clinic and significantly reduce the incidence and number of deaths related to TNBC.

项目概要该提案将研究有助于最重要疾病之一进展的分子驱动因素。侵袭性和转移性乳腺癌。三阴性乳腺癌（TNBC）的特点是缺乏激素受体（雌激素和孕激素）和 HER2 表达，约占占所有乳腺癌的 20%。由于其异质性和缺乏明确的特定分子靶点，TNBC 治疗仍然具有挑战性。因此，本研究旨在阐明分泌载体的分子作用- 相关膜蛋白 3 (SCAMP3) 对 TNBC 发病机制的影响，目标是开发新疗法这将提高患者的生存率。最近，SCAMP3被发现过度表达并与肝细胞癌、黑色素瘤、神经胶质瘤和乳腺癌的预后较差，这表明 SCAMP3 在肿瘤发生中发挥关键作用。然而，SCAMP3促进TNBC的分子机制的进展知之甚少。 SCAMP3 是表皮生长因子受体 (EGFR) 运输的调节剂在内体膜内促进受体再循环。 EGFR介导的内吞作用是一种机制癌症相关信号蛋白的运输，例如信号转导子和转录激活子 3 （统计3）。 EGFR 和 STAT3 与 TNBC 增殖、侵袭、转移和癌症相关干细胞（CSC）维护。我们的目标是确定 SCAMP3 促进的机制 TNBC 进展并确定 SCAMP3/EGFR 和 STAT3 信号通路之间的相互作用。我们假设：1) SCAMP3/EGFR 介导的内吞作用调节 STAT3 的激活。 2）SCAMP3 信号通路通过 EGFR/STAT3 的调节促进和维持 TNBC 干性，3) SCAMP3 有助于 TNBC 肿瘤的形成和转移。为了检验这些假设，我们提出以下目标： 1）阐明SCAMP3对STAT3激活的作用机制； 2) 定义角色 SCAMP3 通过 STAT3 调节进行 TNBC 和 CSC 调节：2a) 阐明其分子机制 SCAMP3在CSC体外维持中的作用； 2b) 研究SCAMP3在肿瘤发生中的作用和转移。我们提出了监测 EGFR 和 STAT3 内化、STAT3 DNA 结合的实验活性和转录活性。我们将确定维持癌症干性的相关驱动基因使用 RNAseq 过度表达 SCAMP3 细胞，这将在患者样本中得到证实。这些研究有有潜力迅速转化为临床并显着降低相关死亡的发生率和数量到 TNBC。