Association between different levels of lipid metabolism­related enzymes and fatty acid synthase in Wilms' tumor.

Wilms' tumor is one of the most common malignant tumors of the abdomen in children. However, there is currently no recognized specific biomarker for the clinical diagnosis and prognosis of this tumor. Lipid metabolism is involved in membrane synthesis and oxidation in tumor cells. This process plays an important role in the development of tumors, but it has not yet been investigated in Wilms' tumor. The aim of the present study was to characterize the changes in lipid metabolism and to contribute to the diagnosis and prognosis of Wilms' tumor. Proteomics analysis was performed to detect lipid­metabolizing enzymes in 9 tissue samples from Wilms' tumors and adjacent tissues, and proteomics revealed the presence of 19 differentially expressed lipid­metabolizing enzymes. Protein interaction analysis with the Search Tool for the Retrieval of Interacting Genes/Proteins was used to identify the interacting proteins. Immunohistochemistry (IHC), immunofluorescence and western blotting were used to further confirm whether the expression of fatty acid synthase (FASN) was significantly increased in the tumor tissues. Oncomine database and reverse transcription­PCR analyses further confirmed that the expression of FASN at the gene level was significantly increased in the tumors. Following collection of 65 pediatric cases of Wilms' tumor at the Shandong Provincial Hospital between 2007 and 2012, the association between the expression of FASN and the clinical characteristics was analyzed, and IHC analysis further demonstrated that FASN expression was significantly associated with tumor stage and size. The association between FASN and the prognosis of children with Wilms' tumor was analyzed using Kaplan­Meier survival curves. In addition, univariate survival analysis revealed that higher expression of FASN in Wilms' tumors was associated with poorer prognosis. Our findings revealed that FASN may be used as a prognostic biomarker in patients with Wilms' tumor. Furthermore, lipid metabolism may play an important role in the occurrence and development of Wilms' tumor.

Acetone immersion enhanced MALDI-MS imaging of small molecule metabolites in biological tissues.

Profiling the endogenous tissue metabolites with spatial features is significant for our understanding of molecular histology, and provides an insightful way to uncover the complex associations between tissue metabolic response and external stimuli. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) is an effective molecular imaging technology to illustrate the spatial locations of molecules in tissue. However, due to the limited sensitivity and the presence of multiple matrix-related ions, it is still challenging to globally image the small molecule metabolites (SMMs) using MALDI, especially for those low-content functional ones. Here, a simple acetone washing method was developed to improve the sensitivity of MALDI-MS for imaging SMMs. After immersing in acetone and shaken for 15 min, key functional SMMs were well-visualized with significantly enhanced ion intensities. In addition to lipids, more than 160 SMM ions, including polyamines, cholines, carnitines, amino acids, nitrogenous bases, nucleosides, carbohydrates, organic acids, vitamins were imaged. The acetone washes-based MALDI-MSI was then applied to profile the metabolic alternations that occurred in osteosarcoma, and the abnormally altered SMMs and lipids were clearly visualized. Moreover, with the protection of acetone against tissue antigenicity, we successfully characterized the expression of three metabolites-related enzymes, fatty acid synthase (FASN), glutaminase (GLS), and cytosolic phospholipase A2 (cPLA2) in osteosarcoma. The spatially-resolved metabolite and corresponding enzyme information reveals what occured in osteosarcoma at the molecular level, providing new insights into the understanding of tumour metabolic reprogramming.

In vivo evidence on the functional variation within fatty acid synthase gene associated with lipid metabolism in bovine longissimus dorsi muscle tissue.

In Korean cattle, intramuscular fat (IMF), or marbling, of the longissimus dorsi muscle (LM) cross section is one of the most important indicators of beef quality and are influenced by environmental and genetic factors. This study was to evaluate the effect of SNPs on the beef quality in Korean cattle for functional studies, such as site-directed mutagenesis based on bovine adipocytes. The fatty acid synthase (FASN) gene plays an important role in lipogenesis. FASN is an essential metabolic and multifunctional enzyme in fatty acid synthesis. Several studies have reported that SNPs g.841G, g.16024A, g.16039T, and g.17924G have a significant impact on marbling scores in Korean cattle and Japanese Black cattle population. These SNPs are located in transcription factor binding sites, the beta-ketoacyl reductase, and thioesterase domains. Our results revealed that the g.17924 A>G SNP is located in the thioesterase domain of the FASN protein, and changes from polar, neutral, and hydrophilic to nonpolar, aliphatic, and hydrophobic, respectively. In in vivo LM tissue of Korean cattle, the g.17924A>G SNP has an effect on increasing fat deposition. Therefore, g.17924A>G SNP could be a causal mutation for increasing fat deposition in Korean cattle LM tissue.

Fatty Acid Synthase and Acetyl-CoA Carboxylase Are Expressed in Nodal Metastatic Melanoma But Not in Benign Intracapsular Nodal Nevi.

BACKGROUND: Melanoma is a potentially lethal form of skin cancer for which the current standard therapy is complete surgical removal of the primary tumor followed by sentinel lymph node biopsy when indicated. Histologic identification of metastatic melanoma in a sentinel node has significant prognostic and therapeutic implications, routinely guiding further surgical management with regional lymphadenectomy. While melanocytes in a lymph node can be identified by routine histopathologic and immunohistochemical examination, the distinction between nodal nevus cells and melanoma can be morphologically problematic. Previous studies have shown that malignant melanoma can over-express metabolic genes such as fatty acid synthase (FASN) and acetyl-CoA carboxylase (ACC). This immunohistochemical study aims to compare the utility of FASN and ACC in differentiating sentinel lymph nodes with metastatic melanomas from those with benign nodal nevi in patients with cutaneous melanoma. MATERIALS AND METHODS: Using antibodies against FASN and ACC, 13 sentinel lymph nodes from 13 patients with metastatic melanoma and 14 lymph nodes harboring benign intracapsular nevi from 14 patients with cutaneous malignant melanoma were examined. A diagnosis of nodal melanoma was based on cytologic atypia and histologic comparison with the primary melanoma. All nodal nevi were intracapsular and not trabecular. Immunohistochemistry for Melan-A, S100, human melanoma black 45 (HMB45), FASN, and ACC were performed. The percentage of melanocytes staining with HMB45, FASN, and ACC was determined and graded in 25% increments; staining intensity was graded as weak, moderate, or strong. RESULTS: All metastatic melanomas tested had at least 25% tumor cell staining for both FASN and ACC. Greater than 75% of the tumor cells stained with FAS in 7/13 cases and for ACC in 5/12 cases. Intensity of staining was variable; strong staining for FASN and ACC was observed in 69% and 50% of metastatic melanoma, respectively. HMB45 was negative in 40% of nodal melanoma cases all of which stained with FASN and ACC. Capsular nevi were uniformly negative for FASN, ACC, and HMB45 immunoreactivity. CONCLUSIONS: All metastatic melanoma cases involving sentinel lymph nodes were positive for FASN and ACC while no staining was observed in intracapsular nevi. These findings suggest that FASN and ACC could be used as valuable ancillary stains in the distinction between nodal nevi and metastatic melanoma.

Targeting fatty acid synthase with ASC-J9 suppresses proliferation and invasion of prostate cancer cells.

Fatty acid synthase (FASN) is the key enzyme for the control of fatty acid synthesis that contributes significantly to the prostate cancer (PCa) progression. It was reported that androgens were able to induce FASN expression in PCa, and addition of the anti-androgen Casodex might suppress the androgen-induced FASN expression. However, here we found androgen-deprivation-therapy (ADT) with anti-androgens Bicalutamide (Casodex) or Enzalutamide (MDV3100) had little effect to suppress FASN expression and FASN-mediated cell growth and invasion during the castration resistant stage when the androgen concentration is 1 nM DHT (dihydrotestosterone). In contrast, the newly developed androgen receptor (AR) degradation enhancer ASC-J9® suppressed FASN expression and FASN-mediated cell growth and invasion in various PCa cell lines at 1 nM DHT. Mechanism dissection found ASC-J9® could suppress significantly the FASN expression and FASN-mediated PCa progression via the AR-dependent pathway involving AR→SREBP-1→FASN signaling in AR-positive C4-2 and LNCaP cells and via the AR-independent pathway involving the modulation of PI3K/AKT→SREBP-1→FASN signaling in AR-negative PC-3 and DU145 cells. Together, these results suggest that FASN is one of the important mechanism why the current ADT eventually fails. ASC-J9® might represent a new potential therapeutic approach to suppress FASN-mediated PCa progression via both AR-dependent and AR-independent pathways during the castration resistant stage of PCa. © 2016 Wiley Periodicals, Inc.

Expression of Fatty Acid Synthase Negatively Correlates with PTEN and Predicts Peritoneal Dissemination of Human Gastric Cancer.

BACKGROUND: This study aimed to examine the clinical significance of fatty acid synthase (FASN) expression in gastric cancer (GC), and investigate any prognostic role. MATERIALS AND METHODS: FASN expression was assessed in gastric cancers by immunohistochemistry using 60 paraffin-embedded tissue specimens, and clinical data were collected by retrospective chart review. Moreover, FASN mRNA expression in 15 fresh resected specimens was evaluated by the reverse transcription-polymerase chain reaction (RT-PCR). Immunohistochemical staining of PTEN was performed to assess the correlation of PTEN with FASN in gastric cancer. RESULTS: Increased expression of FASN was noted in gastric cancers. The frequency of FASN gene amplification was also significantly higher in gastric cancer than in adjacent normal tissue. FASN expression in human gastric cancer tissues was significantly correlated with patient TNM stage and peritoneal dissemination (p<0.05). Moreover, higher FASN expression significantly correlated with shorter overall survival (p<0.05). Here, upregulation of FASN negatively correlated with PTEN expression in gastric cancer. CONCLUSIONS: These findings indicate that FASN expression is upregulated in gastric cancer, and increased FASN may be critical to th peritoneal metastasis and survival. Our results suggest that FASN upregulation and PTEN downregualtion may be involved in peritoneal dissemination for gastric cancer progression.

FASN expression, angiogenesis and lymphangiogenesis in central and peripheral giant cell lesions

Central giant cell lesion (CGCL) and peripheral giant cell lesion (PGCL) are non-neoplastic proliferative processes of the jaws. PGCL is a reactive process induced by irritant local factors and CGCL is an intra-osseous lesion of unknown etiology. Both lesions exhibit similar histologic features showing abundant mononuclear cells, admixed with a large number of multinucleated giant cells and a rich vascularized stroma with extravasated erythrocytes, hemosiderin deposition, and blood-filled pools. Recent studies have linked fatty acid synthase (FASN) with angiogenesis. Objective: To evaluate angiogenesis and lymphangiogenesis and their relationship with FASN expression in CGCL and PGCL. Material and Methods: Thirteen CGCL and 14 PGCL of the jaws were selected for immunoexpression of FASN; CD34 and CD105 (to assess blood microvessel density [MVD] and microvessel area [MVA]); and D2-40 (to assess lymphatic MVD and MVA). Results: Within PGCL and CGCL, MVD-CD34 was signifcantly higher than MVD-CD10S, followed by MVD-D2-40. Moreover, a signifcantly higher number of FASN-positive multinucleated giant cells than mononuclear cells were observed. Between PGCL and CGCL, only MVD-CD34 and all MVA were signifcantly higher in PGCL. Positive correlation between MVA-CD10S with FASNpositive mononuclear cells in both lesions was observed. Conclusions: Our results show both lesions exhibiting similar levels of FASN expression and neoangiogenesis, suggesting constitutive processes that regulate tissue maintenance. .

FASN expression, angiogenesis and lymphangiogenesis in central and peripheral giant cell lesions.

UNLABELLED: Central giant cell lesion (CGCL) and peripheral giant cell lesion (PGCL) are non-neoplastic proliferative processes of the jaws. PGCL is a reactive process induced by irritant local factors and CGCL is an intra-osseous lesion of unknown etiology. Both lesions exhibit similar histologic features showing abundant mononuclear cells, admixed with a large number of multinucleated giant cells and a rich vascularized stroma with extravasated erythrocytes, hemosiderin deposition, and blood-filled pools. Recent studies have linked fatty acid synthase (FASN) with angiogenesis. OBJECTIVE: To evaluate angiogenesis and lymphangiogenesis and their relationship with FASN expression in CGCL and PGCL. MATERIAL AND METHODS: Thirteen CGCL and 14 PGCL of the jaws were selected for immunoexpression of FASN; CD34 and CD105 (to assess blood microvessel density [MVD] and microvessel area [MVA]); and D2-40 (to assess lymphatic MVD and MVA). RESULTS: Within PGCL and CGCL, MVD-CD34 was signifcantly higher than MVD-CD10S, followed by MVD-D2-40. Moreover, a signifcantly higher number of FASN-positive multinucleated giant cells than mononuclear cells were observed. Between PGCL and CGCL, only MVD-CD34 and all MVA were signifcantly higher in PGCL. Positive correlation between MVA-CD10S with FASNpositive mononuclear cells in both lesions was observed. CONCLUSIONS: Our results show both lesions exhibiting similar levels of FASN expression and neoangiogenesis, suggesting constitutive processes that regulate tissue maintenance.

Prognostic impact of fatty acid synthase expression in upper urinary tract urothelial carcinoma.

OBJECTIVE: Fatty acid synthase has been shown to be highly expressed in various types of cancers with increased tumour aggressiveness. In this study we examined the level of fatty acid synthase expression in surgically resected upper urinary tract urothelial carcinoma specimens and evaluated the relations between fatty acid synthase expression and the patients' pathological features and clinical outcomes. METHODS: Sections of paraffin-embedded tumour specimens from 113 patients who underwent surgical treatment for upper urinary tract urothelial carcinoma were immunostained with a polyclonal fatty acid synthase antibody, and a tumour was considered to have high fatty acid synthase expression if >50% of the cancer cells stained with moderate-to-strong intensity. Associations between fatty acid synthase expression and the patients' pathological parameters and survival were analyzed statistically. RESULTS: During the follow-up time (median: 46.8 months), 61 patients (54.0%) had recurrence and 17 (15.0%) died of upper urinary tract urothelial carcinoma. High fatty acid synthase expression was significantly associated with high tumour grade (P = 0.0273). Patients with high fatty acid synthase expression had significantly worse recurrence-free survival and extravesical-recurrence-free survival than those with low fatty acid synthase expression (P = 0.0171, P = 0.0228, respectively). In multivariate analysis, high fatty acid synthase expression was an independent predictor of shortened recurrence-free survival (P = 0.0220, hazard ratio (HR) = 1.970). CONCLUSIONS: Fatty acid synthase expression in upper urinary tract urothelial carcinoma is an independent predictor for tumour recurrence. Patients with high fatty acid synthase expression in upper urinary tract urothelial carcinoma should be followed carefully and adjuvant therapy for them should be considered.

Extranodal nasal NK/T-cell lymphoma: a rare oral presentation and FASN, CD44 and GLUT-1 expression.

Extranodal natural killer (NK)/T-cell lymphoma is an aggressive malignant tumor with distinctive clinicopathological features, characterized by vascular invasion and destruction, prominent necrosis, cytotoxic lymphocyte phenotype and a strong association with Epstein-Barr virus. Here is reported an extranodal nasal NK/T-cell lymphoma case, involving the maxillary sinus, floor of the orbit, and interestingly extending to the oral cavity through the alveolar bone and buccal mucosa, preserving the palate, leading to a primary misdiagnosis of aggressive periodontal disease. Moreover, this work investigated for the first time the immunohistochemical expression of fatty acid synthase (FASN) and glucose transporter 1 (GLUT-1) proteins in this neoplasia. FASN showed strong cytoplasmatic expression in the neoplastic cells, whereas GLUT-1 and CD44 were negative. These findings suggest that the expression of FASN and the loss of CD44 might be involved in the pathogenesis of the extranodal nasal NK/T-cell lymphoma, and that GLUT-1 may not participate in the survival adaptation of the tumor cells to the hypoxic environment. Further studies with larger series are required to confirm these initial results.

Extranodal Nasal NK/T-Cell Lymphoma: A Rare Oral Presentation and FASN, CD44 and GLUT-1 Expression

Extranodal natural killer (NK)/T-cell lymphoma is an aggressive malignant tumor with distinctive clinicopathological features, characterized by vascular invasion and destruction, prominent necrosis, cytotoxic lymphocyte phenotype and a strong association with Epstein-Barr virus. Here is reported an extranodal nasal NK/T-cell lymphoma case, involving the maxillary sinus, floor of the orbit, and interestingly extending to the oral cavity through the alveolar bone and buccal mucosa, preserving the palate, leading to a primary misdiagnosis of aggressive periodontal disease. Moreover, this work investigated for the first time the immunohistochemical expression of fatty acid synthase (FASN) and glucose transporter 1 (GLUT-1) proteins in this neoplasia. FASN showed strong cytoplasmatic expression in the neoplastic cells, whereas GLUT-1 and CD44 were negative. These findings suggest that the expression of FASN and the loss of CD44 might be involved in the pathogenesis of the extranodal nasal NK/T-cell lymphoma, and that GLUT-1 may not participate in the survival adaptation of the tumor cells to the hypoxic environment. Further studies with larger series are required to confirm these initial results.

O linfoma de células natural killers (NK)/T extranodal é um tumor maligno agressivo com características clinicopatológicas distintas, caracterizadas por invasão e destruição vasculares, necrose proeminente, fenótipo linfocítico citotóxico e uma forte associação com o vírus Epstein-Barr. Relatamos aqui um caso de linfoma de células NK/T nasal extranodal, envolvendo o seio maxilar, assoalho de órbita, e interessantemente estendendo-se para a cavidade oral através do osso alveolar e mucosa vestibular, preservando o palato, levando a um diagnóstico inicial equivocado de doença periodontal agressiva. Ainda, nós investigamos pela primeira vez a expressão imunoistoquímica das proteínas Fatty acid sinthase (FASN) e glucose transporter 1 (GLUT-1) nesta neoplasia. FASN revelou uma forte expressão citoplasmática nas células neoplásicas, enquanto GLUT-1 e CD44 foram negativas. Estes achados sugerem que a expressão de FASN e a perda de CD44 podem estar envolvidas na patogênese do linfoma de células NK/T nasal extranodal, e que GLUT-1 não deve participar da adaptação das células tumorais ao ambiente de hipóxia. Estudos adicionais com séries maiores são necessários para confirmar nossos resultados iniciais.

Usefulness of immunohistochemical expression analysis of metabolic-related molecules in differentiating between intracranial neoplastic and non-neoplastic lesions.

As the histologic features of reactive glial proliferation seen in many non-neoplastic lesions and of diffusely infiltrating gliomas overlap, tumor-specific diagnostic markers are needed. A mutation in isocitrate dehydrogenase 1 (IDH1), the enzyme involved in lipid metabolism and glucose sensing, has been identified in a variety of diffuse gliomas. The expression of fatty acid synthase (FAS), the enzyme responsible for the de novo synthesis of fatty acids, has been examined in several types of tumors including high-grade meningiomas, but not or less examined in normal tissues and benign tumors. We analyzed the expression of mutant IDH1 and FAS proteins in 10 non-neoplastic and 52 neoplastic lesions. Paraffin-embedded samples were immunostained with anti-IDH1R132H and -FAS antibodies. Staining of mutant IDH1 was positive in nine neoplastic lesions (3 diffuse astrocytomas, 2 anaplastic astrocytomas, and 1 oligodendroglioma, oligoastrocytoma, anaplastic oligodendroglioma, and glioblastoma); it was negative in all ten non-neoplastic lesions. Moreover, FAS expression was increased in glioblastomas (83.3%), anaplastic oligodendrogliomas and oligoastrocytomas (80%), and anaplastic astrocytomas (78.9%) compared with non-neoplastic lesions (20%). Immunostaining with mutant IDH1R132H-specific and FAS antibodies may be helpful to differentiate reactive from neoplastic cells in diffuse infiltrative or highly proliferative gliomas.

ErbB receptors and fatty acid synthase expression in aggressive head and neck squamous cell carcinomas.

SUMMARY: Overexpression of ErbB receptors is frequent in head and neck squamous cell carcinomas (HNSCC) and seems to be correlated with tumor progression and metastasis. Fatty acid synthase (FASN), the key lipogenic enzyme responsible for the endogenous synthesis of fatty acids, is regulated by ErbB2 and overexpressed in several human malignancies. METHODS: This study was performed to examine the immunohistochemical expression patterns of ErbB1, ErbB2, ErbB3, ErbB4, and FASN in a tissue microarray, containing 33 representative areas from aggressive primary HNSCC (whose patients had distant metastasis), and 21 matched lung metastasis. RESULTS: Strong correlation among the expression of ErbB family receptors was found (ErbB1-ErbB2 P = 0.008, ErbB1-ErbB4 P = 0.018, EbB2-ErbB3 P = 0.001, ErbB2-ErbB4 P = 0.006, ErbB3-ErbB4 P=0.012) in the HNSCC. FASN expression was significantly associated with ErbB2 (P = 0.024). Lymphatic permeation was correlated with ErbB3 (P = 0.033) and histological grade with ErbB4 staining (P = 0.050). ErbB1 and ErbB2 were found mainly in patients with smoking habit (P = 0.011 and P = 0.027), and ErbB2 was associated with alcohol consumption and clinical stage (P = 0.014 and P = 0.031). Finally, FASN was overexpressed in lung metastasis, in comparison with matched HNSCC samples (P = 0.006). CONCLUSIONS: The results showed that high FASN immunohistochemical expression is a feature of HNSCC lung metastasis, and ErbB1-ErbB2, ErbB1-ErbB4, ErbB2-ErbB3, ErbB2-ErbB4, and ErbB3-ErbB4 expression levels are correlated in the respective primary tumors, being ErbB2 the preferred coexpression partner of all the other ErbB receptors.

Serous tubal intraepithelial carcinoma upregulates markers associated with high-grade serous carcinomas including Rsf-1 (HBXAP), cyclin E and fatty acid synthase.

Serous tubal intraepithelial carcinoma (STIC) has been proposed as a precursor for many pelvic high-grade serous carcinomas. Our previous analysis of the ovarian cancer genome identified several genes with oncogenic potential that are amplified and/or overexpressed in the majority of high-grade serous carcinomas. Determining whether these genes are upregulated in STICs is important in further elucidating the relationship of STICs to high-grade serous carcinomas and is fundamental in understanding the molecular pathogenesis of high-grade serous carcinomas. In this study, 37 morphologically defined STICs were obtained from 23 patients with stage IIIC/IV high-grade serous carcinomas. Both STICs and the high-grade serous carcinomas were analyzed for expression of Rsf-1 (HBXAP), cyclin E, fatty acid synthase (FASN) and mucin-4. In addition, they were examined for expression of established markers including p53, Ki-67 and p16. We found that diffuse nuclear p53 and p16 immunoreactivity was observed in 27 (75%) of 36 and 18 (55%) of 33 STICs, respectively, whereas an elevated Ki-67 labeling index (>or=10%) was detected in 29 (78%) of 37 STICs. Cyclin E nuclear staining was seen in 24 (77%) of 35 STICs, whereas normal tubal epithelial cells were all negative. Increased Rsf-1 and FASN immunoreactivity occurred in 63%, and 62% of STICs, respectively, compared with adjacent normal-appearing tubal epithelium. Interestingly, only one STIC showed increased mucin-4 immunoreactivity. Carcinomas, when compared with STICs, overexpressed p16, Rsf-1, cyclin E and FASN in a higher proportion of cases. In conclusion, STICs express several markers including Rsf-1, cyclin E and FASN in high-grade serous carcinomas. In contrast, mucin-4 immunoreactivity either did not change or was reduced in most STICs. These results suggest that overexpression of Rsf-1, cyclin E and FASN occurs early in tumor progression.

[Immunohistochemical algorithms in prostate diagnostics: what's new?]. / Immunhistochemische Algorithmen in der Prostatadiagnostik: Was gibt es Neues?

Immunohistochemistry has become an indispensible tool in biopsy diagnostics of prostate tissues. In particular the use of basal cell markers can be useful to differentiate benign and malignant lesions as a lack of basal cells is considered a hallmark of malignancy. Basal cell cytokeratins and p63 have therefore a long standing place in the diagnostic portfolio of most genito-urinary pathologists. However, to complement the use of these negative markers by additional positive immunohistochemistry markers of malignancy would be desirable to further increase diagnostic accuracy. The most widely used positive marker is alpha-methylacyl-CoA racemase (AMACR), which is strongly upregulated in prostate cancer and which can even be combined with p63 in a single immunostaining. This article briefly and critically reviews current diagnostic prostate cancer biomarkers and also suggests golgi phosphoprotein 2 (GOLPH2) and fatty acid synthase (FASN) as additional diagnostic markers.

[An immunohistochemical study of aromatase, estrogen 4-hydroxylase and fatty acid synthetase in breast cancer tissues from BRCA1 mutation carriers].

Breast cancer in germline BRCA1 mutation carriers features a peculiar endocrine and metabolic profile which is yet to be studied properly in clinical settings. We used a novel immunohistochemical method to compare expression levels of aromatase, estrogen 4-hydroxylase (CYP1B1) and fatty acid synthetase in breast cancer tissues from 12 BRCA1 mutation carriers and 22 non-carriers. Rates of aromatase in carriers were significantly higher than in control (p=0.04) to match the data obtained earlier in cell lines employed in down-regulation of the wild BRCA1 gene. These findings make a case for use of aromatase inhibitors in such patients. No differences in CYP1B1 and fatty acid synthetase expression levels were found between the mutation and the wild BRCA1 gene groups. Further search is warranted for manifestations of excess genotoxic effects of estrogens and enhanced lipogenesis in BRCA1 mutation carriers.

Cohort study of fatty acid synthase expression and patient survival in colon cancer.

PURPOSE: Energy balance seems to be important in the pathogenesis of colon cancer. Fatty acid synthase (FASN) is physiologically regulated by energy balance and is often upregulated in colorectal cancer. Nonetheless, the influence of FASN expression on patient outcome is uncertain. PATIENTS AND METHODS: Using the database of 647 patients with colon cancer in two independent cohort studies, FASN overexpression was detected in 84 tumors (13%) by immunohistochemistry. Cox proportional hazards models calculated hazard ratios (HRs) of colon cancer-specific and overall mortalities, adjusted for patient characteristics and related tumoral features, including KRAS, BRAF, p53, microsatellite instability and the CpG island methylation phenotype. RESULTS: There were 279 deaths, including 160 colon cancer-specific deaths. FASN overexpression was associated with a significant reduction in colon cancer-specific mortality by both univariate and multivariate analyses (adjusted HR, 0.41; 95% CI, 0.19 to 0.89) and an insignificant trend toward improved overall mortality (adjusted HR, 0.75; 95% CI, 0.50 to 1.13). Notably, the effect of FASN expression on mortality might be different according to body mass index (BMI; P(interaction) = .019); the adjusted HR of overall mortality for FASN overexpression was 0.63 (95% CI, 0.39 to 1.02) among patients with BMI less than 27.5 kg/m(2) and 2.91 (95% CI, 1.19 to 7.12) among those with BMI >or= 27.5 kg/m(2). Moreover, the adverse effect of moderate overweight/obesity on overall survival was limited to FASN-positive tumors (adjusted HR, 4.10; 95% CI, 1.14 to 14.8; BMI >or= 27.5 kg/m(2) v < 27.5 kg/m(2)). CONCLUSION Among nonobese patients with colon cancer, tumoral FASN overexpression is associated with improved survival, whereas among moderately overweight or obese patients (BMI >or= 27.5 kg/m(2)), FASN overexpression may predict a worse outcome.