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Characterization of Altered Fatty Acid Trafficking in Triple-Negative Breast Cancer

三阴性乳腺癌中脂肪酸运输改变的特征

基本信息

批准号：
9976321
负责人：
Jeremy Williams
金额：
$ 4.06万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-03 至 2023-01-02
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9976321
关键词：
Apoptosis Attenuated Autophagocytosis Binding Biochemistry and Cellular Biology Bioenergetics Biological Assay Breast Cancer Cell Breast Cancer cell line CRISPR interference Cancer Etiology Carbon Cell Proliferation Cell Survival Cell physiology Cells Cellular Metabolic Process Cessation of life Clinical Clinical Treatment Cultured Tumor Cells Data Defect Diagnosis ERBB2 gene Estrogen Antagonists Ethics Fatty Acids Genetic Glucose Glutamine Goals Growth Homeostasis Human Immunocompromised Host Impairment In Vitro Intervention Investigation Label Ligands Light Lipids Malignant Neoplasms Mass Spectrum Analysis Metabolic Metabolic Pathway Metabolism Microscopy Mitochondria Modeling Molecular Molecular Chaperones Mus Normal Cell Oncogenes Oxygen Consumption Pathway interactions Patients Pharmacology Play Primary Neoplasm Proliferation Marker Proto-Oncogenes Regulation Role Sampling Therapeutic Time Tissue Microarray Transgenic Mice Transplantation Tumor Cell Line United States Up-Regulation Woman Xenograft procedure base c-myc Genes cancer diagnosis cancer subtypes cancer type carcinogenesis endoplasmic reticulum stress experimental study fatty acid metabolism fatty acid oxidation fatty acid-binding proteins glucose metabolism in vivo insight knock-down lipid metabolism malignant breast neoplasm metabolomics mortality mouse model new therapeutic target novel overexpression oxidation receptor small molecule therapeutic target trafficking triple-negative invasive breast carcinoma tumor tumor growth tumorigenesis

项目摘要

PROJECT SUMMARY/ABSTRACT Breast cancer is the most diagnosed cancer type and the second leading cause of cancer-related death in women in the United States. For the receptor positive (RP) subtype comprising the majority of diagnoses, clinical interventions have been largely effective in limiting associated mortality when compared with other cancers. However, the remaining 20%, which comprise the triple-negative breast cancer (TNBC) subtype, lack known therapeutic targets and are the most clinically challenging. Cancers display altered metabolism upon carcinogenesis. However, the efficacy of targeting metabolism in cancer depends upon understanding metabolic dysregulation in the context of a specific oncogene. Our lab and others have shown that levels of c-MYC (MYC), a proto-oncogene that dynamically regulates numerous cellular functions during transformation, are increased in a majority of TNBC. MYC is known to regulate glucose and glutamine metabolism in cancer, but our lab has shown that MYC regulates another important bioenergetic pathway, fatty acid oxidation (FAO), in TNBC. Models for MYC-overexpressing TNBC display decreased bioenergetic metabolism and primary tumor growth upon inhibition of FAO, indicating novel reliance on that pathway. Here, we propose to investigate how TNBC permit increased FAO. Increased FAO necessitates alterations to fatty acid (FA) availability, and one fatty acid trafficking component, fatty acid binding protein 5 (FABP5), is upregulated in TNBC in a MYC-dependent manner. FABPs are lipid chaperones that bind cytosolic FA and other molecules, and can access a range of cellular compartments. Our data indicate that FABP5 loss in MO-TNBC is sufficient to cause defects in cell metabolism and proliferation. FABP5 may contribute to altered FAO and proliferation by facilitating increased FA supply at the mitochondria to permit increased oxidation. We hypothesize that increased trafficking of FA to the mitochondria by FABP5 facilitates altered FAO in a MYC-dependent manner. Accordingly, we propose investigation of the cellular biology and biochemistry of FA trafficking, FABP5 regulation and FAO in TNBC. Our strategy combines: utilization of high-content microscopy to visualize FA trafficking in vitro, carbon-tracing studies to follow FA metabolism in vivo and in vitro, mass spectrometry-based metabolomic analyses, pharmacological and genetic perturbations of FA trafficking, and conditional and constitutive MO-TNBC cell lines and tumor models. We expect that our investigation of mechanisms of FAO in MO-TNBC will advance understanding of how FA metabolism is regulated in cancer, and may identify novel therapeutic targets for the treatment of this clinically challenging breast cancer subtype.

项目总结/文摘