Document Detail


Inhibition of tumor-associated fatty acid synthase hyperactivity induces synergistic chemosensitization of HER -2/ neu -overexpressing human breast cancer cells to docetaxel (taxotere).
MedLine Citation:
PMID:  14999148     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Javier A Menendez; Ruth Lupu; Ramon Colomer
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Breast cancer research and treatment     Volume:  84     ISSN:  0167-6806     ISO Abbreviation:  Breast Cancer Res. Treat.     Publication Date:  2004 Mar 
Date Detail:
Created Date:  2004-03-04     Completed Date:  2004-06-17     Revised Date:  2013-05-28    
Medline Journal Info:
Nlm Unique ID:  8111104     Medline TA:  Breast Cancer Res Treat     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  183-95     Citation Subset:  IM    
Affiliation:
Department of Medicine, Evanston Northwestern Healthcare Research Institute, Evanston, IL 60201, USA. javiermenendez@yahoo.com
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MeSH Terms
Descriptor/Qualifier:
Antifungal Agents / administration & dosage
Antineoplastic Agents, Phytogenic / administration & dosage*
Breast Neoplasms / drug therapy,  genetics
Cell Division / drug effects
Cell Line, Tumor
Cerulenin / administration & dosage
Drug Resistance, Neoplasm / genetics*
Fatty Acid Synthetase Complex / antagonists & inhibitors*
Female
Genes, erbB-2 / genetics*
Humans
Taxoids / administration & dosage*
Transfection
Chemical
Reg. No./Substance:
0/Antifungal Agents; 0/Antineoplastic Agents, Phytogenic; 0/Taxoids; 15H5577CQD/docetaxel; 17397-89-6/Cerulenin; EC 6.-/Fatty Acid Synthetase Complex

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