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：
10408726
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 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10408726
关键词：
Address Biology Biomedical Research Breast Cancer Cell Breast Cancer Patient Breast Cancer Treatment Breast Epithelial Cells Cell Maintenance 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 Investigation Janus kinase Knowledge Lesion MCF10A cells MDA-MB-468 Malignant Neoplasms Medicine Membrane Membrane Proteins Molecular Molecular Target Monitor Mus Neoplasm Metastasis Nuclear Pathogenesis Pathway interactions Patients Phosphorylation Primary carcinoma of the liver cells Productivity Progesterone Prognosis Proteins Publishing Regulation Relapse Reporting Research Role SCID Mice Sampling Signal Pathway Signaling Protein Stat3 protein Survival Rate Testing Therapeutic Therapeutic Agents Time Translating Work breast cancer progression cancer cell cancer stem cell 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.

项目摘要该提议将调查有助于最大的进展的分子驱动因素乳腺癌的侵略性和转移性类型。三重阴性乳腺癌（TNBC）的特征是缺乏激素受体（雌激素和孕酮）和HER2表达，并且约为所有乳腺癌的20％。由于其异质性和所定义特定分子靶标的缺乏，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 TNBC发病机理上相关的膜蛋白3（SCAMP3），目的是开发新疗法这将提高患者的存活率。最近，发现SCAMP3过表达并相关肝细胞癌，黑色素瘤，神经胶质瘤和乳腺癌的预后不良，表明 SCAMP3在肿瘤发生中具有关键作用。但是，SCAMP3如何促进TNBC的分子机制进展知之甚少。 SCAMP3是表皮生长因子受体（EGFR）运输的调节剂在促进受体回收的内体膜内。 EGFR介导的内吞作用是癌症相关信号蛋白的转运，例如信号换能器和转录活化剂3 （Stat3）。 EGFR和STAT3与TNBC增殖，侵袭，转移和癌症有关干细胞（CSC）维护。我们的目标是确定SCAMP3促进的机制 TNBC进程并确定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的调制促进和维持TNBC茎，3） SCAMP3有助于TNBC肿瘤形成和转移。为了检验这些假设，我们提出了以下目的：1）阐明SCAMP3对STAT3激活的作用机理； 2）定义角色 TNBC中的SCAMP3和CSCS通过STAT3调制：2a）阐明了分子机制在体外CSC维护中的SCAMP3； 2b）研究SCAMP3在肿瘤发生和转移。我们提出的实验将监测EGFR和STAT3内在化，STAT3 DNA结合活动和转录活性。我们将确定维持癌症干性的相关驱动基因 SCAMP3使用RNASEQ过表达细胞，该细胞将在患者样品中得到确认。研究有可能会迅速转化为诊所，并显着减少与死亡相关的发病率和数量到TNBC。