Fatty acid Synthase (FAS) expression in human breast cancer cell culture supernatants and in breast cancer patients
Department of Pathology, Johns Hopkins Medical Institutions, 600 N. Wolfe Street/Meyer B-121, Baltimore, MD 21287, USA. Cancer Letters
(Impact Factor: 5.62).
06/2001; 167(1):99-104. DOI: 10.1016/S0304-3835(01)00464-5
Fatty acid synthase (FAS) is selectively expressed in certain human cancers, including carcinoma of the breast, prostate, colon, ovary, and endometrium, compared to normal human tissues and therefore is a putative tumor marker. In this study, we found FAS concentrations were elevated in cell culture supernatants during cell growth in two human breast cancer cell lines but not other cancer cell lines. A quantitative enzyme-linked immunosorbent assay and Western blot analysis were employed in this study. In addition, serum FAS levels were significantly higher in breast cancer patients with different clinical stages (Stage II: 0.59+/-0.09 units/l, Stage III: 0.79+/-0.13 units/l, and Stage IV: 1.39+/-0.35 units/l) compared with healthy subjects (0.27+/-0.02 units/l, P<0.05). Taken together, our data suggest that FAS expression may be a useful tumor marker for breast cancer and play a role in assessing cancer virulence.
Available from: Linda Koshy
- "FASN expression is drastically increased under pathological conditions , and it has been associated with the development of a variety of diseases including cardiovascular disease , insulin resistance of type 2 diabetes  and many types of cancers . FASN overexpression has been reported in several cancers, including glioma , breast , prostate , colon , and lung  cancer , compared with their respective normal tissue. Recently, FASN expression was shown to be notably upregulated in inducible pluripotent stem (iPS) cells, and pharmacological inhibition of FASN activity markedly decreased the reprogramming efficiency of iPS cells  . "
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ABSTRACT: Cellular metabolic changes, especially to lipid metabolism, have recently been recognized as a hallmark of various cancer cells. However, little is known about the significance of cellular lipid metabolism in the regulation of biological activity of glioma stem cells (GSCs). In this study, we examined the expression and role of fatty acid synthase (FASN), a key lipogenic enzyme, in GSCs. In the de novo lipid synthesis assay, GSCs exhibited higher lipogenesis than differentiated non-GSCs. Western blot and immunocytochemical analyses revealed that FASN is strongly expressed in multiple lines of patient-derived GSCs (G144 and Y10), but its expression was markedly reduced upon differentiation. When GSCs were treated with 20 μM cerulenin, a pharmacological inhibitor of FASN, their proliferation and migration were significantly suppressed and de novo lipogenesis decreased. Furthermore, following cerulenin treatment, expression of the GSC markers nestin, Sox2 and fatty acid binding protein (FABP7), markers of GCSs, decreased while that of glial fibrillary acidic protein (GFAP) expression increased. Taken together, our results indicate that FASN plays a pivotal role in the maintenance of GSC stemness, and FASN-mediated de novo lipid biosynthesis is closely associated with tumor growth and invasion in glioblastoma.
Available from: Helga Ogmundsdottir
- "In 1994 Kuhajda and colleagues reported that a protein (oncogenic antigen-519) linked to poor prognosis in breast cancer was identical to FASN (Kuhajda et al. 1994). Since then FASN has been shown to be up-regulated in a variety of cancers such as breast (Vazquez- Martin et al. 2008; Wang et al. 2001), prostate (Migita et al. 2009) and colon (Notarnicola et al. 2012). The mechanism behind the FASN overexpression is not completely understood but sex steroid hormones and their receptor (Chalbos et al. 1987; Menendez et al. 2005b) as well as the human epidermal growth factor receptor 2 (HER2) (Kumar-Sinha et al. 2003; Vazquez-Martin et al. 2009) have been shown to have an important role involving the mitogen activated protein (MAP) kinase and phosphatidylinositol (PI) 3-kinase signalling cascades (Yang et al. 2002). "
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The lichen compound (+)-protolichesterinic acid (+)-PA, isolated from Iceland moss, has anti-proliferative effects on several cancer cell lines. The chemical structure of (+)-PA is similar to a known fatty acid synthase (FASN) inhibitor C75.
To test whether the anti-proliferative activity of (+)-PA is associated with effects on FASN and HER2 (human epidermal growth factor receptor 2) and major signalling pathways. Synergism between (+)-PA and lapatinib, a HER2 active drug, was also evaluated.
Materials and methods
Pure compound was isolated by preparative high-performance liquid chromatography (HPLC) and purity of (+)-PA analyzed by analytical HPLC. Cell viability was assessed using Crystal violet staining. FASN and HER2 expression was estimated by immunofluorescence. The Meso Scale Discovery (MSD)® assay was used to measure activation of ERK1/2 and AKT. Synergism was estimated by the CalcuSyn software.
Treatment with (+)-PA increased FASN expression in SK-BR-3 cells, which overexpress FASN and HER2, implying a compensatory response to inhibition of FASN activity. HER2 expression was decreased suggesting secondary downregulation. ERK1/2 and AKT signalling pathways were inhibited, probably due to reduced levels of HER2. No effects were observed in T-47D cells. Synergism between (+)-PA and lapatinib was observed in the SK-BR-3 cells.
Results suggest that the primary effect of (+)-PA is inhibition of FASN activity. Synergistic effects with lapatinib were seen only in SK-BR-3 cells, and not T-47D cells, further supporting the notion that (+)-PA acts by inhibiting FASN with secondary effects on HER2 expression and signalling. (+)-PA could therefore be a suitable agent for further testing, alone or in combination treatment against HER2-overexpressing breast cancer.
Available from: sapub.org
- "Basic and clinical studies on human cancer have found high levels of de novo fatty acid synthase (FAS). It has been identified immunohistochemically in cancers of the breast  , colon, prostate, ovary , and endometrium. Lipoprotein lipase (LPL) catalyses the hydrolysis of the triacylglycerol component of circulating chylomicrons and very low density lipoproteins, thereby providing non-esterified fatty acids and 2-monoacylglycerol for tissue utilization. "
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