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Fatty Acid Synthase:Molecular Target for Breast Cancer Therapy & Chemoprevention

脂肪酸合成酶：乳腺癌治疗的分子靶点

基本信息

批准号：
7476258
负责人：
RUTH LUPU
金额：
$ 7.05万
依托单位：
NORTHSHORE UNIVERSITY HEALTHSYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-16 至 2008-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7476258
关键词：
Accounting Acidity Address Affect Anabolism Angiogenic Factor Animals Anthracycline Antibiotics Anthracyclines Apoptosis Attenuated Behavior Biogenesis Biological Assay Biopsy Breast Breast Cancer Cell Breast Cancer Model Breast Cancer Treatment Breast Carcinoma Cancer Etiology Cancer Patient Cancer cell line Carcinoma Cell Death Cell membrane Cell model Cells Cerulenin Chemicals Chemoprevention Clinical Code Commit Complex Cultured Cells Cytotoxic agent Data Development Diagnosis Diagnostic Neoplasm Staging Diet Dietary Fatty Acid Disease Down-Regulation Drug resistance Early Intervention Employee Strikes Engineering Epigenetic Process Epithelial Epithelial Cells Equilibrium Event Evolution Exhibits Exposure to Extracellular Domain Fatty Acids Fatty acid glycerol esters Fatty-acid synthase Fibroblasts Gene Amplification Gene Expression Gene Expression Profiling Gene Targeting Genes Growth Human Hyperactive behavior Hypersensitivity Hypoxia Immunotherapy Impairment In Vitro Incubated Inhibition of Apoptosis Invasive Laboratories Lesion Link Lipids MEKs Maintenance Malignant - descriptor Malignant Neoplasms Mammary Neoplasms Measurement Mediating Membrane Messenger RNA Metabolic Minor Modification Molecular Molecular Target Mus Mycotoxins Nature Neoplasm Metastasis Neoplastic Cell Transformation Noninfiltrating Intraductal Carcinoma Normal Cell Normal tissue morphology Obesity Oleic Acid Oleic Acids Oncogene Proteins Oncogenes Oncogenic P-Glycoprotein P-Glycoproteins PEA3 PI3K/AKT Pathway interactions Pharmacologic Substance Phase Phenotype Physiological Play Population Study Predictive Value Premalignant Prevention Protein Overexpression Protein Tyrosine Kinase Proteins Proteomics RNA Interference Ras/Raf Rate Receptor Protein-Tyrosine Kinases Regulation Relative (related person)Reporting Research Research Personnel Resistance Risk Roche brand of trastuzumab Role Score Serum Signal Transduction Small Interfering RNA Small RNA Solid Neoplasm Source Staging Stream Testing Therapeutic Tissues Transcriptional Activation Transfection Trastuzumab Treatment Protocols Tumorigenicity Up-Regulation Vascular Endothelial Growth Factors Vinorelbine angiogenesis base breast lesion cancer cell cancer risk cancer therapy cell growth cell injury cell killing cellular engineering chemotherapy clinically relevant cytotoxicity docetaxel fatty acid biosynthesis gene repression hormone therapy humanized monoclonal antibodies hypoxia inducible factor 1 in vivo inhibitor/antagonist lipid biosynthesis lobular breast carcinoma in situ malignant breast neoplasm malignant phenotype neoplastic neoplastic cell novel novel therapeutics orlistat outcome forecast prognostic promoter prospective response sensor therapeutic target transcription factor tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): There are two sources of fatty acids for animals, exogenous (dietary) fatty acids and de novo endogenous biosynthesis, of which the latter is regulated by Fatty Acid Synthase (FAS). The high level of fat in the Western diet has been implicated in the development of many human malignancies, including breast cancer. Indeed, dietary fatty acids have emerged as an intense focus of research and controversy in breast cancer etiology, prevention and/or therapy. Human breast cancer cell lines and breast tumors exhibit overexpression and hyperactivity of FAS, with FAS-overexpressing breast cancer tumors demonstrating shortened disease-free intervals or overall survivals. Moreover, FAS overexpression can also be identified in intraductal and lobular in situ breast carcinoma, pre-neoplastic lesions associated with increased risk for the development of infiltrating breast cancer, while elevated serum FAS levels have been identified in breast cancer patients with different clinical stages compared with healthy subjects. Interestingly, the relative absence of endogenous fatty acid biosynthesis in normal tissues has led to the notion that FAS blockade should provide a highly selective basis for anticancer therapy. These data, altogether, reveal that FAS-dependent de novo fatty biogenesis, an anabolic energy-storage pathway largely considered of minor importance in humans, may ultimately be used for diagnosis, prognosis, early intervention, and treatment of breast carcinomas. As a part of our efforts to assess the role of FAS signaling on the survival and proliferation of human breast cancer cells, we have identified a novel bi-directional molecular link between breast cancer-associated FAS and Her-2/neu oncogene. A positive correlation was found between high levels of FAS expression and the amplification and/or overexpression of Her-2/neu oncogene. Pharmacological inhibition of FAS by the natural mycotoxin cerulenin, or a related synthetic compound, C75 or a statin Orlistat, negatively regulated Her-2/neu-encoded p185Her-2/neu oncoprotein and its associated tyrosine-kinase activity. When FAS gene expression was silenced by RNA interference (RNAi) a dramatic decrease of p185Her-2/neu expression occurred in the Her-2/neu-overexpressing cells, whereas there was no effect in cells expressing physiological levels of Her-2/neu. Remarkably, pharmacological and RNAi mediated downregulation of Her-2/neu and, concomitantly, caused a prominent up-regulation of PEA3, a transcriptional represser of Her-2/neu. Furthermore, a simultaneous targeting of FAS and Her-2/neu signaling by chemical FAS inhibitors and the humanized monoclonal antibody directed against p185Her-2/neu trastuzumab (Herceptin(tm)), resulted in a synergistic growth inhibitory effect towards Her-2/neu overexpressing cells. These findings support the hypothesis that breast cancer-associated FAS, rather than simply the epigenetic consequence of aberrant activation of up-stream transduction pathways (e.g. PI-3K/AKT, Ras/Raf/MEK/ERK) plays an active role in breast cancer evolution by regulating oncogenic proteins closely related to malignant transformation. Indeed, our pioneer observations demonstrating the ability of FAS-driven signaling to regulate the expression and/or activity of Her-2/neu (erbB-2) oncogene strongly suggest that FAS may actively participate in the triggering, maintenance and/or enhancement of the breast cancer malignant phenotype. Therefore our aims are: 1) To characterize the molecular mechanism determining the early up-regulation of FAS in breast cancer and to evaluate the oncogenic potential of FAS-catalyzed endogenous lipogenesis in normal breast epithelial cell models. We will determine how FAS contributes to the pre-neoplastic transformation of noncommittal breast epithelial cells (normal cells) and whether FAS overexpression sets off malignant transformation. 2) To evaluate the therapeutic relevance of targeting FAS in Her-2/neu-overexpressing breast cancer in vitro and in vivo on the basis of the novel bidirectional molecular link between FAS and the Her-2/neu that we recently demonstrated. 3) We will characterize the molecular mechanisms underlying the bi-directional molecular cross-talk between FAS and Her-2/neu. In addition, we will assess whether FAS blockade represents a novel sensitizing strategy to reverse trastuzumab (Herceptin(tm)) resistance in Her-2/neu-overexpressing breast carcinomas. 4) To evaluate whether inhibition of FAS activity modulates breast cancer cell sensitivity to chemotherapy-induced cell damage and to evaluate whether silencing FAS expression modulates breast cancer cell sensitivity to chemotherapy-induced cell damage. 5) To determine the molecular relevance and clinical impact of FAS expression in breast cancer progression, and to evaluate the value and clinical contribution to the treatment decision provided by the assessment of circulating serum levels of FAS. Our study speculates that constitutive up-regulation of FAS in breast cancer disease represents an early metabolic response for survival to the hypoxic and acidic microenvironment of pre-malignant breast cancer phases. This epigenetic up-regulation of FAS in early stages of breast cancer may result, in turn, in a metabolic strategy of selection to maintain high proliferation rates of surviving cells. The characterization of FAS as a novel metabolic oncogene will allow an invaluable adjunct to gene expression profiling or proteomics in the characterization of biologically aggressive subsets of breast carcinomas. Moreover, the predictive potential of measurement FAS expression will help in the selection of better responders to cytotoxic drugs, and Her-2/neu-targeted therapies. Considering that drug resistance hampers successful breast cancer treatment, and its prevention or reversal is still awaiting new sensitizing strategies or pharmaceuticals, our study will open a new molecular avenue based on the specific targeting of FAS-dependent neoplastic lipogenesis, a valuable specific molecular target that is minimally activated in normal tissues.