Fatty acid synthase inhibitors are chemopreventive for mammary cancer in neu-N transgenic mice.
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 p21(waf1) 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.
Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Patricia M
PM
Alli
Michael L
ML
Pinn
Elizabeth M
EM
Jaffee
Jill M
JM
McFadden
Francis P
FP
Kuhajda
D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D004268:DNA-Binding Proteins; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors*; D005260:Female; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000254:growth & development; D015674:Mammary Neoplasms, Animal / Q000517:prevention & control*; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D014407:Tumor Cells, Cultured; D019014:fas Receptor
C406734:4-methylene-2-octyl-5-oxofuran-3-carboxylic acid; D004268:DNA-Binding Proteins; C491899:Fas protein, mouse; D009419:Nerve Tissue Proteins; C492380:NeuN protein, mouse; D009687:Nuclear Proteins; D018124:Receptors, Tumor Necrosis Factor; D019014:fas Receptor; D064429:Fatty Acid Synthases; D015107:4-Butyrolactone