The lipogenic enzyme fatty acid synthase (FAS) is differentially overexpressed and hyperactivated in a biologically 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 (c- erb B-2) oncogene and FAS has been described in human breast cancer cells. 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-resistant SK-Br3 cells, modest synergism in moderately HER -2/ neu -expressing MCF-7 cells, and it showed additive effects in low HER -2/ neu -expressing and docetaxel-sensitive MDA-MB-231 cells. Sequential exposure to cerulenin followed by docetaxel again yielded strong synergism in SK-Br3 cells, whereas antagonistic and moderate synergistic interactions were observed in MCF-7 and MDA-MB-231 cells, respectively. Importantly, inhibition of FAS activity 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 breast cancer chemotherapy resistance.