2004
DOI: 10.1073/pnas.0403390101
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Abstract: Fatty acid synthase (FAS) activity is a potential therapeutic target to treat cancer and obesity. Here, we have identified a molecular link between FAS and HER2 (erbB-2) oncogene, a marker for poor prognosis that is overexpressed in 30% of breast and ovarian cancers. Pharmacological FAS inhibitors cerulenin and C75 were found to suppress p185 HER2 oncoprotein expression and tyrosinekinase activity in breast and ovarian HER2 overexpressors. Similarly, p185 HER2 expression was dramatically down-regulated when FA… Show more

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Cited by 304 publications
(300 citation statements)
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“…Previous studies from our group revealed that pharmacological blockade of FASN activity using the natural compound cerulenin, the cerulenin-derived semi-synthetic anti-metabolite C75, or the ß-lactone Orlistat, significantly repressed HER2 protein expression in cancer cells naturally bearing HER2 gene amplification (22)(23)(24)(25)(26)(27)(28)(29). Real-time polymerase chain reaction (RT-PCR) studies showed that down-regulation of HER2 mRNA levels closely correlated with FASN blockade-induced reduction of HER2 protein expression, thus suggesting that changes in HER2 oncogene expression upon pharmacological inhibition of FASN activity resulted from effects at the transcriptional level (22). Indeed, FASN inhibition was found to up-regulate the expression of the Ets class transcription factor PEA3, a potent trans-repressor of HER2 promoter activity that specifically reverses the in vitro transformed phenotype of HER2-overexpressing cancer cells and inhibits HER2-induced tumorigenesis in vivo (30)(31)(32)(33).…”
Section: Pharmacological Blockade Of Fatty Acid Synthase (Fasn) Revermentioning
confidence: 96%
See 1 more Smart Citation
“…Previous studies from our group revealed that pharmacological blockade of FASN activity using the natural compound cerulenin, the cerulenin-derived semi-synthetic anti-metabolite C75, or the ß-lactone Orlistat, significantly repressed HER2 protein expression in cancer cells naturally bearing HER2 gene amplification (22)(23)(24)(25)(26)(27)(28)(29). Real-time polymerase chain reaction (RT-PCR) studies showed that down-regulation of HER2 mRNA levels closely correlated with FASN blockade-induced reduction of HER2 protein expression, thus suggesting that changes in HER2 oncogene expression upon pharmacological inhibition of FASN activity resulted from effects at the transcriptional level (22). Indeed, FASN inhibition was found to up-regulate the expression of the Ets class transcription factor PEA3, a potent trans-repressor of HER2 promoter activity that specifically reverses the in vitro transformed phenotype of HER2-overexpressing cancer cells and inhibits HER2-induced tumorigenesis in vivo (30)(31)(32)(33).…”
Section: Pharmacological Blockade Of Fatty Acid Synthase (Fasn) Revermentioning
confidence: 96%
“…Nonetheless, unraveling the ultimate mechanisms underlying resistance to Tzb-based therapy in human cancer is a major challenge that is beginning to be addressed, and this dilemma is becoming increasingly important as recent studies strongly support a role for Tzb in the adjuvant setting for HER2-overexpressing early-stage breast cancers (19)(20)(21). Previous studies from our group revealed that pharmacological blockade of FASN activity using the natural compound cerulenin, the cerulenin-derived semi-synthetic anti-metabolite C75, or the ß-lactone Orlistat, significantly repressed HER2 protein expression in cancer cells naturally bearing HER2 gene amplification (22)(23)(24)(25)(26)(27)(28)(29). Real-time polymerase chain reaction (RT-PCR) studies showed that down-regulation of HER2 mRNA levels closely correlated with FASN blockade-induced reduction of HER2 protein expression, thus suggesting that changes in HER2 oncogene expression upon pharmacological inhibition of FASN activity resulted from effects at the transcriptional level (22).…”
Section: Pharmacological Blockade Of Fatty Acid Synthase (Fasn) Revermentioning
confidence: 99%
“…Downstream of the growth factors and steroid receptors, the phosphatidylinositol-3-kinase (PI3K)/Akt, and mitogen-activated protein kinase (MAPK) signaling pathways have been suggested to mediate FAS expression through the sterol regulatory element-binding protein 1c (SREBP-1c) [13,18]. However, the up-regulation of FAS by activated growth factor receptors requires a complex signaling network [19,20]. Indeed, recent reports have shown that FAS expression is controlled not only by SREBP-1c but also by other transcription factors, such as the p53 family proteins and the lipogenesis-related nuclear protein, SPOT14, which is often overexpressed in breast tumor [21,22].…”
Section: Introductionmentioning
confidence: 99%
“…12 This work raises the possibility of pharmacologically targeted inhibition of FASN as a potential breast cancer therapy. If and when such studies in humans become feasible, correlation with FASN protein expression in tumors will need to be closely examined, and may have some significance to therapy response.…”
Section: Discussionmentioning
confidence: 93%
“…8,9 In breast cancer, some investigators have reported an association between FASN expression and tumor recurrence. 10,11 There may also be a regulatory effect of FASN on the expression of the nearby (17q21) Her2neu gene 12 and a recent study raises the possibility of cancer chemoprevention by inhibition of FASN. 13 We have generated a novel rabbit polyclonal antiserum to the FASN gene and describe the immunohistochemical expression in normal, precancerous and cancerous breast.…”
mentioning
confidence: 99%