Genomes and Genes
Fatty Acid Synthase:Molecular Target for Breast Cancer Therapy & Chemoprevention
Principal Investigator: Ruth Lupu
Affiliation: Mayo Clinic
Abstract: 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.
Funding Period: 2005-09-16 - 2010-05-31
more information: NIH RePORT
- Pharmacological inhibitors of Fatty Acid Synthase (FASN)--catalyzed endogenous fatty acid biogenesis: a new family of anti-cancer agents?Ruth Lupu
Department of Medicine, Evanston Northwestern Healthcare Research Institute, Evanston, IL 60201, USA
Curr Pharm Biotechnol 7:483-93. 2006..5 A resolution X-ray crystallographic map of mammalian FASN, will direct the foundation of a new family of chemotherapeutic agents in cancer history...
- Oncogenic properties of the endogenous fatty acid metabolism: molecular pathology of fatty acid synthase in cancer cellsJavier A Menendez
Foundation of the Recerca Bio Medical Institute of Girona Dr Josep Trueta, University Hospital of Girona, Dr Josep Trueta, Girona, Catalonia, Spain
Curr Opin Clin Nutr Metab Care 9:346-57. 2006..This review documents our rapidly changing perspectives on the function of fatty acid synthase-catalyzed endogenous fatty acid biogenesis in cancer biology...
- Targeting fatty acid synthase in breast and endometrial cancer: An alternative to selective estrogen receptor modulators?Ruth Lupu
Department of Medicine, Evanston Northwestern Healthcare Research Institute, 1001 University Place, Evanston, Illinois 60201, USA
Endocrinology 147:4056-66. 2006....
- HER2 (erbB-2)-targeted effects of the omega-3 polyunsaturated fatty acid, alpha-linolenic acid (ALA; 18:3n-3), in breast cancer cells: the "fat features" of the "Mediterranean diet" as an "anti-HER2 cocktail"Javier A Menendez
Fundació d Investigació Biomèdica de Girona Dr Josep Trueta IdIBGi, Girona, Catalonia Spain
Clin Transl Oncol 8:812-20. 2006....
- Mediterranean dietary traditions for the molecular treatment of human cancer: anti-oncogenic actions of the main olive oil's monounsaturated fatty acid oleic acid (18:1n-9)Javier A Menendez
Fundació d Investigació Biomèdica de Girona Dr Josep Trueta IdIBGi, Girona, Catalonia, Spain
Curr Pharm Biotechnol 7:495-502. 2006..Only then we will know whether the old "Mediterranean dietary traditions" will become a new molecular approach in the management of cancer disease...
- Fatty acid synthase and the lipogenic phenotype in cancer pathogenesisJavier A Menendez
Translational Research Unit, Catalan Institute of Oncology ICO, Health Services Division of Catalonia, Girona Biomedical Research Institute IdIBGi, Medical Oncology, Josep Trueta University Hospital of Girona, 17, 007 Girona, Catalonia, Spain
Nat Rev Cancer 7:763-77. 2007..FASN, a nearly-universal druggable target in many human carcinomas and their precursor lesions, offers new therapeutic opportunities for metabolically treating and preventing cancer...
- Transphosphorylation of kinase-dead HER3 and breast cancer progression: a new standpoint or an old concept revisited?Javier A Menendez
Catalan Institute of Oncology ICO, Health Services Division of Catalonia, Girona Biomedical Research Institute IdIBGi, Medical Oncology, Dr, Josep Trueta, University Hospital of Girona, Catalonia, Spain
Breast Cancer Res 9:111. 2007....
- An easy, rapid and objective mathematical method to identify fatty acid synthase (oncogenic antigen-519) modulators with potential anticancer valueRuth Lupu
Department of Medicine, Northwestern University Feinberg School of Medicine, Evanston Northwestern Healthcare Research Institute, Evanston, IL 60201, USA
Clin Transl Oncol 10:219-26. 2008..This "C75-sensitivity test" might offer an easy, rapid and objective method to identify FASN inhibitors with potential anticancer value in human cancer...