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Progression of DCIS to Invasive Breast Cancer through CCR2 Chemokine Signaling

通过 CCR2 趋化因子信号转导 DCIS 进展为浸润性乳腺癌

基本信息

批准号：
9887275
负责人：
Nikki Cheng
金额：
$ 41.95万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9887275
关键词：
Animal Model Animals Biochemical Biological Assay Breast Cancer Cell Breast Cancer cell line CCL2 gene Cancer Cell Growth Carcinoma Cell Culture Techniques Cells Chemotaxis Degradation Pathway Development Diagnosis Disease Disease Progression Enzymes FASN gene Fatty Acids Fatty-acid synthase G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs Glucose Glutaminase Glutamine Glycolysis Goals Growth Hexokinase 2 Impairment In Vitro Inflammation Injections Invasive Lesion Lead Magnetic Resonance Imaging Malignant Neoplasms Mammary gland Mass Spectrum Analysis Mediating Metabolic Metabolism Modeling Molecular Noninfiltrating Intraductal Carcinoma Pathway interactions Patients Pattern Pharmacology Proteins Public Health Receptor Protein-Tyrosine Kinases Recurrence Risk Role Sampling Signal Transduction Signaling Protein Tissues Tumor Tissue Woman base breast cancer diagnosis breast cancer survival breast lesion cancer invasiveness cell growth cell motility cellular imaging chemokine chemokine receptor experience imaging approach infiltrating duct carcinoma knock-down macrophage malignant breast neoplasm metabolomics monocyte chemoattractant protein 1 receptor mouse model novel outcome forecast overexpression overtreatment personalized approach predictive marker protein degradation protein expression recruit response spectroscopic imaging therapeutic target transplant model tumor metabolism tumor progression wound closure

项目摘要

ABSTRACT About 50,000 cases of ductal carcinoma in situ (DCIS) are diagnosed in the US every year, making DCIS the most common type of non-invasive breast cancer diagnosed in women. Up to 20% of all patients will experience disease recurrence accompanied by invasive ductal carcinoma (IDC). Current cyto- and histopathological approaches do not accurately predict disease progression, resulting in patients being under-treated or over- treated for DCIS. Our long-term goals are to identify key factors that lead to IDC that will enable the development of a molecular based approach to predict the risk of IDC, and a more tailored approach to treat DCIS. The chemokine receptor CCR2 is a G Protein Coupled Receptor, which is normally expressed on macrophages and regulates chemotaxis in response to CCL2 during inflammation and cancer progression. Using a mammary intraductal injection model (MIND) to mimic DCIS formation in animals, we have challenged current paradigms on CCL2/CCR2 signaling, by demonstrating that CCL2/CCR2 signaling to breast cancer cells promotes DCIS progression to IDC. This R01 renewal project characterizes the role of metabolism and c-MET in CCL2/CCR2 mediated DCIS progression, and may identify better predictive markers for DCIS progression, with implications on reducing patient over-treatment, and provide justification for developing CCR2 as a therapeutic target to reduce under-treatment. Metabolic reprogramming is an important hallmark of cancer, but is poorly understood in early stage breast cancer. Preliminary studies indicate that CCL2/CCR2 enhancement of DCIS progression is associated with increased glycolysis and glutamine metabolism, which facilitate fatty acid synthesis. CCL2 mediated breast cancer invasiveness and metabolism may be dependent on interactions between CCR2 and c- MET receptor tyrosine kinases in breast cancer cells. We hypothesize that CCL2/CCR2 chemokine signaling in breast cancer cells enhances glucose and glutamine metabolism through c-MET dependent mechanisms to facilitate DCIS progression. Aim 1 is to determine the relevance of CCL2, CCR2, c-MET and metabolic enzyme expression to DCIS progression to invasive carcinoma using patient samples and magnetic resonance imaging/spectroscopy approaches in DCIS bearing animals. Aim 2 is to determine the functional contribution of c-MET to CCL2/CCR2 mediated breast cancer growth, survival, invasion and metabolism through modulating c- MET in breast cancer cells in vitro and in the MIND model. Mechanisms of CCR2/c-MET/SRC interactions in breast cancer cell lines will be examined through molecular and biochemical approaches. Aim 3 is to determine the biochemical and molecular mechanisms through which CCL2/CCR2 mediated metabolic changes promote breast cancer growth, survival and invasion through modulation of glycolytic, glutamine and fatty acid synthesis pathways in breast cancer cells in biochemical and cell culture assays. Protein degradation pathways that potentially regulate HKII, GLS1 and FASN expression in breast cancer cells will be examined through biochemical approaches.

摘要