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/nue- overexpressing and docetaxel-resistant SK-Br3 cells, modest synergism in moderately HER-2/nue-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.
Original language | English (US) |
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Pages (from-to) | 183-195 |
Number of pages | 13 |
Journal | Breast Cancer Research and Treatment |
Volume | 84 |
Issue number | 2 |
DOIs | |
State | Published - Mar 1 2004 |
Keywords
- Breast cancer
- Cerulenin
- Chemotherapy
- Docetaxel
- Fatty acid synthase
- HER-2/neu
- Taxotere
ASJC Scopus subject areas
- Oncology
- Cancer Research