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) |
|---|---|
| Pages (from-to) | 183-195 |
| Number of pages | 13 |
| Journal | Breast Cancer Research and Treatment |
| Volume | 84 |
| Issue number | 2 |
| DOIs | |
| State | Published - Mar 2004 |
| Externally published | Yes |
Fingerprint
Keywords
- Breast cancer
- Cerulenin
- Chemotherapy
- Docetaxel
- Fatty acid synthase
- HER-2/neu
- Taxotere
ASJC Scopus subject areas
- Oncology
- Cancer Research
Cite this
Inhibition of tumor-associated fatty acid synthase hyperactivity induces synergistic chemosensitization of HER-2/neu-overexpressing human breast cancer cells to docetaxel (taxotere). / Menendez, Javier A.; Lupu, Ruth; Colomer, Ramon.
In: Breast Cancer Research and Treatment, Vol. 84, No. 2, 03.2004, p. 183-195.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Inhibition of tumor-associated fatty acid synthase hyperactivity induces synergistic chemosensitization of HER-2/neu-overexpressing human breast cancer cells to docetaxel (taxotere)
AU - Menendez, Javier A.
AU - Lupu, Ruth
AU - Colomer, Ramon
PY - 2004/3
Y1 - 2004/3
N2 - 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.
AB - 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.
KW - Breast cancer
KW - Cerulenin
KW - Chemotherapy
KW - Docetaxel
KW - Fatty acid synthase
KW - HER-2/neu
KW - Taxotere
UR - http://www.scopus.com/inward/record.url?scp=1642296150&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=1642296150&partnerID=8YFLogxK
U2 - 10.1023/B:BREA.0000018409.59448.60
DO - 10.1023/B:BREA.0000018409.59448.60
M3 - Article
VL - 84
SP - 183
EP - 195
JO - Breast Cancer Research and Treatment
JF - Breast Cancer Research and Treatment
SN - 0167-6806
IS - 2
ER -