Breast Cancer Research and Treatment 84: 183–195, 2004. © 2004 Kluwer Academic Publishers. Printed in the Netherlands. Brief communication Inhibition of tumor-associated fatty acid synthase hyperactivity induces synergistic chemosensitization of HER-2/neu-overexpress human breast cancer cells to docetaxel (taxotere) Javier A. Menendez 1,2 , Ruth Lupu 1,2 , and Ramon Colomer 3 1 Department of Medicine, Evanston Northwestern Research Institute, Evanston; 2 The Feinberg School of Medicine, Northwestern University, Chicago, IL, USA; 3 Medical Oncology, Hospital Josep Trueta, Institut Catala d’Oncologia, Girona, Spain Key words: breast cancer, cerulenin, chemotherapy, docetaxel, fatty acid synthase, HER-2/neu, taxotere Summary The lipogenic enzyme fatty acid synthase (FAS) is differentially overexpressed and hyperactivated in a b aggressive subset of breast carcinomas and minimally in most normal adult tissues, rendering it an interesting target for antineoplastic therapy development. Recently, a molecular connection between the HER-2/neu 2) oncogene and FAS has been described in human breast cancer cells [1]. Here,we examined the relationship between breast cancer-associated FAS hyperactivity and HER-2/neu-induced breast cancer chemoresistance to taxanes. Co-administration of docetaxel (Taxotere ® ) and the mycotoxin cerulenin, a potent and non-competitive inhibitor of FAS activity, demonstrated strong synergism in HER-2/neu-overexpressing and docetaxel-resista SK-Br3 cells, modest synergism in moderately HER-2/neu-expressing MCF-7 cells, and it showed additiv in low HER-2/neu-expressing and docetaxel-sensitive MDA-MB-231 cells. Sequential exposure to cerulenin fol- lowed by docetaxel again yielded strong synergism in SK-Br3 cells, whereas antagonistic and moderate interactions were observed in MCF-7 and MDA-MB-231 cells, respectively. Importantly, inhibition of FA dramatically decreased the expression of HER-2/neu oncogene in SK-Br3 breast cancer cells. To the best of our knowledge this is the first study demonstrating that FAS is playing an active role in HER-2/neu-induced cancer chemotherapy resistance. A biologically aggressive subset of human breast can- cers is characterized to exhibit derangement of the de novo fatty acid biosynthesis, manifested as over- expression and hyperactivity of the lipogenic enzyme fatty acid synthase (FAS) [2–8]. Most human tissues express very low levels of FAS since endogenous fatty acid biosynthesis is down-regulated when a normal diet is consumed [9–10]. This differential expression of FAS between normal and breast cancer cells has lead to the hypothesis that breastcancer-associated FAS hyperactivity could be exploited as a target for the development of new therapeutic antimetabolites [5, 8, 11]. In particular, the tumoricidal activity of pharmacological inhibitors of FAS activity has be- gun to emerge. It has been demonstrated that cer- ulenin [(2R, 3S), 2-3-epoxy-4-oxo-7, 10- trans, trans- dodecadienamide], a natural product derived from the fungus Cephalosporium caerulens that binds irrever- sibly to the catalytic binding site of the β-ketoacyl car- rier protein synthase in the multienzyme FAS complex [12–16], leads to selective cytotoxicity of breast can- cer cells in vitro [17–20]. In vivo, treatment with cer- ulenin has resulted in significantly increased survival in human cancer xenografts [21]. A more stable FAS inhibitor, the α-methylene-γ-butyrolactone C75, has recently become available [22]. Similarly to cerulenin, C75 inhibits the activity of FAS, induces cytostatic and cytotoxic effects against cultured breast cancer cells, and exhibits significant growth inhibitory effects on human breast cancer xenografts [19, 22].