Inhibition of tumor-associated fatty acid synthase hyperactivity induces synergistic chemosensitization of HER-2/neu-overexpressing human breast cancer cells to docetaxel (taxotere)

Javier A. Menendez, Ruth Lupu, Ramon Colomer

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59 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)183-195
Number of pages13
JournalBreast Cancer Research and Treatment
Volume84
Issue number2
DOIs
StatePublished - Mar 2004
Externally publishedYes

Fingerprint

docetaxel
Fatty Acid Synthases
Breast Neoplasms
Cerulenin
Neoplasms
Oncogenes
Taxoids
Mycotoxins
MCF-7 Cells
Antineoplastic Agents

Keywords

  • Breast cancer
  • Cerulenin
  • Chemotherapy
  • Docetaxel
  • Fatty acid synthase
  • HER-2/neu
  • Taxotere

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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title = "Inhibition of tumor-associated fatty acid synthase hyperactivity induces synergistic chemosensitization of HER-2/neu-overexpressing human breast cancer cells to docetaxel (taxotere)",
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{\circledR}) 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.",
keywords = "Breast cancer, Cerulenin, Chemotherapy, Docetaxel, Fatty acid synthase, HER-2/neu, Taxotere",
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AU - Colomer, Ramon

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