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Fatty acid synthase inhibitors are chemopreventive for mammary cancer in neu-N transgenic mice

Abstract

High levels of fatty acid synthase (FAS) have been found in cancer precursor lesions of the colon, stomach, esophagus, oral cavity, prostate, and breast. Inhibition of FAS with C75 has led to a significant antitumor effect in both human breast and prostate cancer xenografts. Recently, HER2/neu, which has also been identified in preneoplastic breast lesions, has been shown to regulate FAS expression through the PI3K/Akt signal transduction pathway rendering them susceptible to FAS inhibition. Utilizing the neu-N transgenic mouse model of mammary cancer, weekly treatment of the neu-N mice with C75 (30 mg/kg) for 10 weeks significantly delayed tumor progression. Only 20% of the C75-treated transgenic mice developed mammary carcinoma by 220 days, compared to 50% in the vehicle control animals. Two C75-treated animals never developed mammary cancer. Analysis of mammary tissue following 10 weeks of C75 treatment revealed a significant delay in mammary maturation as manifested by a reduction of the number and caliber of mammary ducts and budding epithelial structures. Apoptotic changes were increased, DNA synthesis was decreased, and the expressions of FAS, neu, Akt, phospho-Akt, and p21waf1 were all decreased when compared to vehicle controls and FVB/N mice. Importantly, these effects were restricted to the breast epithelial cells that overexpressed neu, not involving other normal duct structures in the skin, liver, or kidney. C247, an FAS inhibitor chemically distinct from C75, significantly delayed mammary maturation similar to C75. Thus, pharmacological inhibition of FAS affects the expression of key oncogenes involved in both cancer development and maintenance of the malignant phenotype. Moreover, these data identify FAS as a potential novel drug target for breast cancer chemoprevention.

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Acknowledgements

This work was supported by DOD Grant DAMD 17-02-1-0430 to PMA and FPK, and NIH Grants CA87850 to FPK and NIH/NCI NCDDG 2U19CA72108, Spore in Breast Cancer 1P50CA88843 to EMJ, and an SBIR NCI Grant # 1R44CA99435 to FASgen Inc. Dr Jaffee is the Dana and Albert ‘Cubby’ Broccoli Professor of Oncology. Funding for the study described in this article was also provided by FASgen, LLC. Under a licensing agreement between FASgen and the Johns Hopkins University, FPK is entitled to a share of royalty received by the University on sales of products described in this article. FPK owns FASgen stock, which is subject to certain restrictions under University policy. The Johns Hopkins University, in accordance with its conflict of interest policies, is managing the terms of this arrangement.

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Correspondence to Francis P Kuhajda.

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Alli, P., Pinn, M., Jaffee, E. et al. Fatty acid synthase inhibitors are chemopreventive for mammary cancer in neu-N transgenic mice. Oncogene 24, 39–46 (2005). https://doi.org/10.1038/sj.onc.1208174

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