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Inhibition of Tumor-associated Fatty Acid Synthase Hyperactivity Induces Synergistic Chemosensitization of HER-2/neu-Overexpressing Human Breast Cancer Cells to Docetaxel (taxotere)

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Abstract

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-erbB-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-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.

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Authors and Affiliations

  1. Department of Medicine, Evanston Northwestern Research Institute, Evanston

    Javier A. Menendez & Ruth Lupu

  2. The Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    Javier A. Menendez & Ruth Lupu

  3. Medical Oncology, Hospital Josep Trueta, Institut Catala d'Oncologia, Girona, Spain

    Ramon Colomer

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  1. Javier A. Menendez
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  2. Ruth Lupu
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Menendez, J.A., Lupu, R. & Colomer, R. Inhibition of Tumor-associated Fatty Acid Synthase Hyperactivity Induces Synergistic Chemosensitization of HER-2/neu-Overexpressing Human Breast Cancer Cells to Docetaxel (taxotere). Breast Cancer Res Treat 84, 183–195 (2004). https://doi.org/10.1023/B:BREA.0000018409.59448.60

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