Fatty Acid Synthase (Fas) Predictive Strength in Poorly Differentiated Early Breast Carcinomas

Alò, Piero Luigi; Visca, Paolo; Trombetta, Giorgio; Mangoni, Antonella; Lenti, Luisa; Monaco, S.; Botti, Claudio; Serpieri, D Eleuteri; Tondo, U. Di

doi:10.1177/030089169908500108

Cited by 106 publications

(33 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In one of these, there was a 9-fold increased risk of death when high levels of FAS expression occurred together with a high proliferative index (>17%). 54,55 A total of 17 cytoskeletal-associated proteins with diverse biological functions were significantly up-regulated in ERα+ breast tumors (Suppl. Table S7a).…”

Section: Discussionmentioning

confidence: 99%

Differential Protein Expression Profiles in Estrogen Receptor-Positive and -Negative Breast Cancer Tissues Using Label-Free Quantitative Proteomics

et al. 2010

View full text Add to dashboard Cite

Identification of the proteins that are associated with estrogen receptor (ER) status is a first step towards better understanding of the hormone-dependent nature of breast carcinogenesis. Although a number of gene expression analyses have been conducted, protein complement has not been systematically investigated to date. Because proteins are primary targets of therapeutic drugs, in this study, we have attempted to identify proteomic signatures that demarcate ER-positive and -negative breast cancers. Using highly enriched breast tumor cells, replicate analyses from 3 ERα+ and 3 ERα− human breast tumors resulted in the identification of 2,995 unique proteins with ≥2 peptides. Among these, a number of receptor tyrosine kinases and intracellular kinases that are abundantly expressed in ERα+ and ERα− breast cancer tissues were identified. Further, label-free quantitative proteome analysis revealed that 236 proteins were differentially expressed in ERα+ and ERα− breast tumors. Among these, 141 proteins were selectively up-regulated in ERα+, and 95 proteins were selectively up-regulated in ERα− breast tumors. Comparison of differentially expressed proteins with a breast cancer database revealed 98 among these have been previously reported to be involved in breast cancer. By Gene Ontology molecular function, dehydrogenase, reductase, cytoskeletal proteins, extracellular matrix, hydrolase, and lyase categories were significantly enriched in ERα+, whereas selected calcium-binding protein, membrane traffic protein, and cytoskeletal protein were enriched in ERα− breast tumors. Biological process and pathway analysis revealed that up-regulated proteins of ERα+ were overrepresented by proteins involved in amino acid metabolism, proteasome, and fatty acid metabolism, while up-regulated proteins of ERα− were overrepresented by proteins involved in glycolysis pathway. The presence and relative abundance of 4 selected differentially abundant proteins (liprin-α1, fascin, DAP5, and β-arrestin-1) were quantified and validated by immunohistochemistry. In conclusion, unlike in vitro cell culture models, the in vivo signaling proteins and pathways that we have identified directly from human breast cancer tissues may serve as relevant therapeutic targets for the pharmacological intervention of breast cancer. KeywordsLC-MS/MS, breast cancer, estrogen receptor, laser capture microdissection, fascin

show abstract

Section: Discussionmentioning

confidence: 99%

Differential Protein Expression Profiles in Estrogen Receptor-Positive and -Negative Breast Cancer Tissues Using Label-Free Quantitative Proteomics

et al. 2010

View full text Add to dashboard Cite

show abstract

“…Western blot analysis was done as described previously (12)(13)(14). Briefl y, cell lysates were separated by SDS-polyacrylamide gel electrophoresis followed by transfer to a PVDF membrane.…”

Section: Cell Lysate Preparation and Western Blot Analysismentioning

confidence: 99%

“…Overexpression of FASN has been associated with poor prognosis and higher risk of recurrence of human cancers of the breast (9)(10)(11)(12) and prostate ( 13 ), as well as many other types of cancers ( 1 ), suggesting that increased FASN expression may also contribute to disease progression and treatment failure. In particular, FASN overexpression has been found in a drug-selected breast cancer cell line, and this elevation contributes to cellular resistance to Adriamycin (doxorubicin) and mitoxantrone in breast ( 14 ) and to gemcitabine in pancreatic cancer cells ( 15 ).…”

mentioning

confidence: 99%

Fatty acid synthase causes drug resistance by inhibiting TNF-α and ceramide production

Liu

Dong

et al. 2013

Journal of Lipid Research

View full text Add to dashboard Cite

This article is available online at http://www.jlr.org in normal nonadipose tissues/cells. Cancer cells, however, synthesize more than 90% of their triacylglycerol de novo, requiring increased FASN expression ( 1 ). The important role of FASN in cancer cell proliferation/survival and its potential oncogenic function have been demonstrated in several previous studies ( 2-8 ).Overexpression of FASN has been associated with poor prognosis and higher risk of recurrence of human cancers of the breast ( 9-12 ) and prostate ( 13 ), as well as many other types of cancers ( 1 ), suggesting that increased FASN expression may also contribute to disease progression and treatment failure. In particular, FASN overexpression has been found in a drug-selected breast cancer cell line, and this elevation contributes to cellular resistance to Adriamycin (doxorubicin) and mitoxantrone in breast ( 14 ) and to gemcitabine in pancreatic cancer cells ( 15 ). However, the mechanism by which FASN contributes to drug resistance is currently unknown.In this study, we investigated the molecular mechanism of FASN-mediated drug resistance using FASN overexpression stable clones of MCF7 cells and found that FASN overexpression causes resistance to multiple anticancer drugs as well as to ␥ -irradiation via inhibiting treatmentinduced ceramide production, caspase 8 activation, and apoptosis. Further studies showed that FASN overexpression suppresses tumor necrosis factor (TNF)-␣ production, nuclear factor (NF)-B activation, and drug-induced activation of neutral sphingomyelinase (nSMase). Hence, FASN overexpression may cause drug resistance by inhibiting TNF-␣ expression, which in turn suppresses activation of NF-B and nSMase and, thus, reduced ceramide production, caspase 8 activation, and apoptosis.Abstract Fatty acid synthase (FASN) is a key enzyme in the synthesis of palmitate, the precursor of major nutritional, energetic, and signaling lipids. FASN expression is upregulated in many human cancers and appears to be important for cancer cell survival. Overexpression of FASN has also been found to associate with poor prognosis and higher risk of recurrence of human cancers. Indeed, elevated FASN expression has been shown to contribute to drug resistance. However, the mechanism of FASN-mediated drug resistance is currently unknown. In this study, we show that FASN overexpression causes resistance to multiple anticancer drugs via inhibiting drug-induced ceramide production, caspase 8 activation, and apoptosis. We also show that FASN overexpression suppresses tumor necrosis factor-␣ production and nuclear factor-B activation as well as drug-induced activation of neutral sphingomyelinase. Thus, TNF-␣ may play an important role in mediating FASN function in drug resistance. Mammalian FASN is a homo-dimer of a multifunctional protein of ‫ف‬ 270 kDa containing seven catalytic domains: ␤ -ketoacyl synthase, malonyl/acetyltransferase, dehydrogenase, enoyl reductase, ␤ -ketoacyl reductase, acyl carrier protein, and thioesterase . Under normal physiologi...

show abstract

“…In addition to affecting adipogenesis, fatty acids produced by FAS are known to stimulate other signaling pathways, including autophagy and miRNA signaling ( 63,64 ). FAS has also received much attention regarding the regulation of its activity during cancer development (19)(20)(21)(22)(23). As a key enzyme regulating energy metabolism and as a metabolic oncogene, FAS has been considered as a potential target for the development of antiobesity and anti-cancer drugs.…”

Section: Discussionmentioning

confidence: 99%

“…

…”

mentioning

confidence: 99%

S-nitrosylation of fatty acid synthase regulates its activity through dimerization

Choi

Jung

Kim

et al. 2016

Journal of Lipid Research

View full text Add to dashboard Cite

reported that FAS is involved in the regulation of adipose tissue mass ( 1, 10-18 ), a key enzyme regulating energy metabolism, and a metabolic oncogene ( 19,20 ). Therefore, FAS has been considered as a potential target for the development of anti-obesity and anti-cancer drugs (21)(22)(23)(24)(25). Expression of FAS is transcriptionally regulated by the sterol regulatory element-binding protein-1c (SREBP-1c) and by upstream stimulatory factors 1 and 2 (USF1 and USF2) in response to feeding or to insulin ( 26,27 ). So far, however, nothing is known about the posttranslational modifi cation of FAS except that it is ubiquitinated ( 28,29 ).NO is a critical signaling molecule that is involved in a number of physiological and pathological processes. When overproduced, NO is known to have harmful effects on cell function and survival ( 30-32 ). In contrast, within the physiological concentration range, NO plays a critical role as a regulator of cellular signaling pathways ( 33-35 ). A major mechanism mediating the biological function of NO is protein S-nitrosylation, a posttranslational modifi cation of proteins involving the addition of an NO + to a cysteine thiol group of the proteins. Therefore, under physiological conditions, S-nitrosylation can affect a number of cellular signaling pathways by inducing conformational changes of the protein and affecting protein-protein interactions and protein functions (36)(37)(38)(39). NO is reported to improve the ␤ -oxidation of fatty acids through reversible protein S-nitrosylation ( 40 ). NO is also known to impair the antilipolytic action of insulin in obesity through S-nitrosylation ( 41 ) and to enhance adipogenesis in primary human preadipocytes ( 42 ). However, little is known about the target proteins of S-nitrosylation during adipogenesis.Abstract NO regulates a variety of physiological processes, including cell proliferation, differentiation, and infl ammation. S-nitrosylation, a NO-mediated reversible protein modifi cation, leads to changes in the activity and function of proteins. In particular, the role of S-nitrosylation during adipogenesis is largely unknown. We hypothesized that the normal physiological levels of NO, but not the excess levels generated under severe conditions, such as infl ammation, may be critically involved in the proper regulation of adipogenesis. We found that endogenous S-nitrosylation of proteins was required for adipocyte differentiation. By performing a biotin-switch assay, we identifi ed FAS, a key lipogenic enzyme in adipocytes, as a target of S-nitrosylation during adipogenesis. Interestingly, we also observed that the dimerization of FAS increased in parallel with the amount of S-nitrosylated FAS during adipogenesis. FAS, which is highly expressed in adipose tissue, liver, and lactating mammary glands, catalyzes the synthesis of palmitate from acetyl-CoA and malonyl-CoA in the presence of NADPH ( 1-3 ). FAS is active as a homodimer, and each monomer has seven separate functional domains, including malonyl/acetyltransferase, ␤ -ket...

show abstract

Fatty Acid Synthase (Fas) Predictive Strength in Poorly Differentiated Early Breast Carcinomas

Abstract: FAS is a reliable prognosticator of recurrence in poorly differentiated early breast carcinomas. Association of FAS with PLVI may be useful to plan a correct follow-up in patients with breast neoplasms.

Cited by 106 publications

References 31 publications

Differential Protein Expression Profiles in Estrogen Receptor-Positive and -Negative Breast Cancer Tissues Using Label-Free Quantitative Proteomics

Differential Protein Expression Profiles in Estrogen Receptor-Positive and -Negative Breast Cancer Tissues Using Label-Free Quantitative Proteomics

Fatty acid synthase causes drug resistance by inhibiting TNF-α and ceramide production

S-nitrosylation of fatty acid synthase regulates its activity through dimerization

Contact Info

Product

Resources

About