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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References
Alo PL, Visca P, Botti C, Galati GM, Sebastiani V, Andreano T, Di Tondo U and Pizer ES . (2001). Am. J. Clin. Pathol., 116, 129–134.
Boggio K, Di Carlo E, Rovero S, Cavallo F, Quaglino E, Lollini PL, Nanni P, Nicoletti G, Wolf S, Musiani P and Forni G . (2000). Cancer Res., 60, 359–364.
Boizard M, Le Liepvre X, Lemarchand P, Foufelle F, Ferre P and Dugail I . (1998). J. Biol. Chem., 273, 29164–29171.
Bull JH, Ellison G, Patel A, Muir G, Walker M, Underwood M, Khan F and Paskins L . (2001). Br. J. Cancer, 84, 1512–1519.
Epstein JI, Carmichael M and Partin AW . (1995). Urology, 45, 81–86.
Fabian CJ . (2001). Breast Cancer Res., 3, 99–103.
Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, Vogel V, Robidoux A, Dimitrov N, Atkins J, Daly M, Wieand S, Tan-Chiu E, Ford L and Wolmark N . (1998). J. Natl. Cancer Inst., 90, 1371–1388.
Guy CT, Webster MA, Schaller M, Parsons TJ, Cardiff RD and Muller WJ . (1992). Proc. Natl. Acad. Sci. USA, 89, 10578–10582.
Jordan VC . (2000). J. Steroid Biochem. Mol. Biol., 74, 269–277.
Kim JB, Sarraf P, Wright M, Yao KM, Mueller E, Solanes G, Lowell BB and Spiegelman BM . (1998). J. Clin. Invest., 101, 1–9.
Krontiras H, Roye GD, Beenken SE, Myers RB, Mayo MS, Peters GE and Grizzle WE . (1999). Head Neck, 21, 325–329.
Kuhajda FP . (2000). Nutrition, 16, 202–208.
Kuhajda FP, Pizer ES, Li JN, Mani NS, Frehywot GL and Townsend CA . (2000). Proc. Natl. Acad. Sci. USA, 97, 3450–3454.
Kumar-Sinha C, Ignatoski KW, Lippman ME, Ethier SP and Chinnaiyan AM . (2003). Cancer Res., 63, 132–139.
Kusakabe T, Nashimoto A, Honma K and Suzuki T . (2002). Histopathology, 40, 71–79.
Lofts FJ and Gullick WJ . (1992). Cancer Treat. Res., 61, 161–179.
Loftus TM, Jaworsky DE, Frehywot GL, Townsend CA, Ronnett GV, Lane MD and Kuhajda FP . (2000). Science, 288, 2379–2381.
McFadden JM, Frehywot GL and Townsend CA . (2002). Org. Lett., 4, 3859–3862.
McFadden JM, Medghalchi SM, Thupari JN, Pinn ML, Vadlamudi A, Miller KI, Kuhajda FP and Townsend CA . (2004). J. Med. Chem. (in review).
Menendez JA, Vellon L, Mehmi I, Oza BP, Ropero S, Colomer R and Lupu R . (2004). Proc. Natl. Acad. Sci. USA, 101, 10715–10720.
Milgraum LZ, Witters LA, Pasternack GR and Kuhajda FP . (1997). Clin. Cancer Res., 3, 2115–2120.
Mueller SO, Clark JA, Myers PH and Korach KS . (2002). Endocrinology, 143, 2357–2365.
Nemoto T, Terashima S, Kogure M, Hoshino Y, Kusakabe T, Suzuki T and Gotoh M . (2001). Pathobiology, 69, 297–303.
Pflug BR, Pecher SM, Brink AW, Nelson JB and Foster BA . (2003). Prostate, 57, 245–254.
Pizer ES, Pflug BR, Bova GS, Han WF, Udan MS and Nelson JB . (2001). Prostate, 47, 102–110.
Pizer ES, Thupari J, Han WF, Pinn ML, Chrest FJ, Frehywot GL, Townsend CA and Kuhajda FP . (2000). Cancer Res., 60, 213–218.
Pizer ES, Wood FD, Heine HS, Romantsev FE, Pasternack GR and Kuhajda FP . (1996). Cancer Res., 56, 1189–1193.
Rashid A, Pizer ES, Moga M, Milgraum LZ, Zahurak M, Pasternack GR, Kuhajda FP and Hamilton SR . (1997). Am. J. Pathol., 150, 201–208.
Reilly RT, Emens LA and Jaffee EM . (2001a). Curr. Opin. Investig. Drugs, 2, 133–135.
Reilly RT, Gottlieb MB, Ercolini AM, Machiels JP, Kane CE, Okoye FI, Muller WJ, Dixon KH and Jaffee EM . (2000). Cancer Res., 60, 3569–3576.
Reilly RT, Machiels JP, Emens LA, Ercolini AM, Okoye FI, Lei RY, Weintraub D and Jaffee EM . (2001b). Cancer Res., 61, 880–883.
Reilly RT, Machiels JP, Emens LA and Jaffee EM . (2002). Methods Mol. Med., 69, 233–257.
Thupari JN, Kim EK, Moran TH, Ronnett GV and Kuhajda FP . (2004). Am. J. Physiol. Endocrinol. Metab., 287, E97–E104.
Thupari JN, Landree LE, Ronnett GV and Kuhajda FP . (2002). Proc. Natl. Acad. Sci. USA, 99, 9498–9502.
Visca P, Alo PL, Del Nonno F, Bottie C, Trombetta G, Marandino F, Filippi S, Di Tondo U and Donnorso RP . (1999). Clin. Cancer Res., 5, 4111–4118.
Wakil SJ . (1989). Biochemistry, 28, 4523–4530.
Wang HQ, Altomare DA and Testa JR . (2003). Proc. Am. Assoc. Cancer Res., 44, 1100.
Weinstein IB . (2002). Science, 297, 63–64.
Xu R, Perle MA, Inghirami G, Chan W, Delgado Y and Feiner H . (2002). Mod. Pathol., 15, 116–124.
Yang YA, Han WF, Morin PJ, Chrest FJ and Pizer ES . (2002). Exp. Cell Res., 279, 80–90.
Zhou BP, Hu MC, Miller SA, Yu Z, Xia W, Lin SY and Hung MC . (2000). J. Biol. Chem., 275, 8027–8031.
Zhou W, Simpson PJ, McFadden JM, Townsend CA, Medghalchi SM, Vadlamudi A, Pinn ML, Ronnett GV and Kuhajda FP . (2003). Cancer Res., 63, 7330–7337.
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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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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DOI: https://doi.org/10.1038/sj.onc.1208174
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