Document text
Principal Investigator: Nikki Cheng
Organization: UNIVERSITY OF KANSAS MEDICAL CENTER
Fiscal Year: 2024
Award: $345,567
Funding agency: National Cancer Institute
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.
Terms: <Animal Model><Animal Models and Related Studies><Animals><Assay><Bioassay><Biochemical><Biological Assay><Body Tissues><Breast Cancer><Breast Cancer Cell><Breast Cancer cell line><Breast Cell Glutaminase><Breast tumor cell line><CCL2><CCL2 gene><CCR2 receptor><Cancer Cell Growth><Cancers><Carcinoma><Cell Body><Cell Communication and Signaling><Cell Culture Techniques><Cell Signaling><Cells><Cellular Expansion><Cellular Growth><Chemokine Receptor Gene><Chemokine, CC Motif, Ligand 2><Chemotactic Cytokines><Chemotaxis><D-Glucose><DCIS><Degradation Pathway><Degradative Pathway><Development><Dextrose><Diagnosis><Disease Progression><Ductal Breast Carcinoma In Situ><Ductal Carcinoma In Situ><EC 2.3.1.85><EC 2.7.1.1><EC 3.5.1.2><Enzyme Gene><Enzymes><Epithelial cancer><FASN><FASN gene><Fatty Acid Synthetase Complex><Fatty Acids><Fatty-acid synthase><G Protein-Complex Receptor><G Protein-Coupled Receptor Genes><G-Protein-Coupled Receptors><GA Protein><GPCR><Generalized Growth><Gln><Glucose><Glutaminase><Glutamine><Glycolysis><Goals><Growth><HK II><HK2 Protein><Hexokinase 2><Hexokinase II><Homologous Chemotactic Cytokines><Impairment><In Vitro><Inflammation><Injections><Intercrines><Intermediary Metabolism><Intracellular Communication and Signaling><Intraductal Carcinoma><Intraductal Carcinoma of the Breast><Invaded><Invasive Lesion><L glutamine amidohydrolase><L-Glutamine><Liver Glutaminase><MCAF><MCP-1><MCP-1 receptor><MCP1><MGC14367><MGC15706><MR Imaging><MR Tomography><MRI><MRIs><Macrophage><Magnetic Resonance Imaging><Malignant Breast Neoplasm><Malignant Epithelial Neoplasms><Malignant Epithelial Tumors><Malignant Neoplasms><Malignant Tumor><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Mediating><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Metabolic><Metabolic Processes><Metabolic Protein Degradation><Metabolism><Modeling><Molecular><Monocyte Chemoattractant Protein-1><Monocyte Chemotactic Protein-1><Monocyte Chemotactic and Activating Factor><Monocyte Chemotactic and Activating Protein><Monocyte Chemotactive and Activating Factor><Monocyte Secretory Protein JE><Motility><Muscle Form Hexokinase><Muscle Hexokinase-2><Mφ><NMR Imaging><NMR Tomography><Non-Infiltrating Ductal Breast Adenocarcinoma><Non-Infiltrating Ductal Carcinoma of the Breast><Non-Infiltrating Intraductal Adenocarcinoma><Non-Infiltrating Intraductal Breast Adenocarcinoma><Non-Invasive Ductal Breast Adenocarcinoma><Non-Invasive Ductal Carcinoma of the Breast><Non-Invasive Intraductal Breast Adenocarcinoma><Noninfiltrating Intraductal Carcinoma><Nuclear Magnetic Resonance Imaging><OA-519><PTK Receptors><Pathway interactions><Patients><Pattern><Personalized medical approach><Predicting Risk><Protein Turnover><Proteins><Public Health><Q Levoglutamide><Q. Levoglutamide><Receptor Protein-Tyrosine Kinases><Receptor Tyrosine Kinase Gene><Recurrent disease><Regulatory Protein Degradation><Relapsed Disease><Role><SCYA2><SIS cytokines><Sampling><Signal Transduction><Signal Transduction Systems><Signaling><Signaling Factor Proto-Oncogene><Signaling Pathway Gene><Signaling Protein><Small Inducible Cytokine A2><Spectroscopy><Spectrum Analyses><Spectrum Analysis><Tissue Growth><Tissues><Transmembrane Receptor Protein Tyrosine Kinase><Tumor Tissue><Type II Hexokinase><Tyrosine Kinase Linked Receptors><Tyrosine Kinase Receptors><Zeugmatography><biological signal transduction><breast cancer diagnosis><breast cancer survival><breast lesion><breast tumor cell><cancer cell metabolism><cancer invasiveness><cancer metabolism><cancer progression><cell culture><cell cultures><cell growth><cell imaging><cellular imaging><chemoattractant cytokine><chemokine><chemokine receptor><developmental><diagnosis among females><diagnosis among women><diagnosis in females><diagnosis in women><diagnosis within females><diagnosis within women><epithelial carcinoma><experience><female diagnosis><forecasting risk><imaging approach><imaging based approach><individualized approach><infiltrating duct carcinoma><infiltrating ductal adenocarcinoma><infiltrating ductal carcinoma><invasive ductal adenocarcinoma><invasive ductal carcinoma><knock-down><knockdown><malignancy><malignant breast tumor><mammary><metabolism measurement><metabolomics><metabonomics><model of animal><monocyte chemoattractant protein 1 receptor><mouse model><murine model><neoplasm progression><neoplasm/cancer><neoplastic progression><novel><ontogeny><over-treatment><overexpress><overexpression><overtreatment><pathway><patient prognosis><personalized approach><pharmacologic><precision approach><predict risk><predict risks><predicted risk><predicted risks><predicting risks><predictive biomarkers><predictive marker><predictive molecular biomarker><predictive risk><predicts risk><protein degradation><protein expression><recruit><response><risk prediction><risk predictions><social role><tailored approach><therapeutic target><transplant model><tumor cell metabolism><tumor metabolism><tumor progression><women's diagnosis><wound closure>