Targeting fatty acid synthase: potential for therapeutic intervention in her-2/neu-overexpressing breast cancer.
Fatty acid synthase (FAS)-catalyzed de novo fatty acid biosynthesis, an anabolic energy-storage pathway largely considered of minor importance in humans, actively contributes to the cancer phenotype by virtue of its ability to specifically regulate the expression and activity of Her-2/neu (erbB-2) oncogene. First, a positive correlation between high levels of FAS expression and/or activity and the amplification and/or overexpression of Her-2/neu oncogene exists in human breast cancer cell lines. Second, Her-2/neu overexpression stimulates the activity of FAS gene promoter and ultimately mediates increased endogenous fatty acid biosynthesis, while this Her-2/neu-induced upregulation of breast cancer-associated FAS is inhibitable by anti-Her-2/neu antibodies such as trastuzumab (Herceptin(TM)). Third, pharmacological inhibition of FAS activity negatively regulates the expression and tyrosine-kinase activity of Her-2/neu-coded p185(Her-2/neu) oncoprotein.
Menendez
Javier A
JA
Department of Medicine, Evanston Northwestern Healthcare Research Institute, Evanston, Illinois 60201, USA. jmenendez@enh.org
Lupu
Ruth
R
Colomer
Ramon
R
D015107:4-Butyrolactone / Q000008:administration & dosage / Q000031:analogs & derivatives; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D002392:Catechin / Q000008:administration & dosage / Q000031:analogs & derivatives; D002569:Cerulenin / Q000008:administration & dosage; D016503:Drug Delivery Systems; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*
D015107:4-Butyrolactone; D000970:Antineoplastic Agents; D002392:Catechin; D002569:Cerulenin; D064429:Fatty Acid Synthases; D018719:Erb-b2 Receptor Tyrosine Kinases; C014096:alpha-methylene gamma-butyrolactone; C045651:epigallocatechin gallate