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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.

项目总结