Gene Summary

Gene:MAS1; MAS1 proto-oncogene, G protein-coupled receptor
Aliases: MAS, MGRA
Summary:This gene encodes a class I seven-transmembrane G-protein-coupled receptor. The encoded protein is a receptor for angiotensin-(1-7) and preferentially couples to the Gq protein, activating the phospholipase C signaling pathway. The encoded protein may play a role in multiple processes including hypotension, smooth muscle relaxation and cardioprotection by mediating the effects of angiotensin-(1-7). [provided by RefSeq, May 2012]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:proto-oncogene Mas
Source:NCBIAccessed: 16 March, 2017


What does this gene/protein do?
Show (26)

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 16 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Melanoma
  • Antigens, CD24
  • Cell Line
  • Egr3 protein, mouse
  • CD24
  • Apoptosis
  • Lymphatic Metastasis
  • Transcription Factors
  • Syk protein, mouse
  • Triple Negative Breast Cancer
  • G-Protein-Coupled Receptors
  • Chromosome Banding
  • Immunohistochemistry
  • Karyotyping
  • DNA
  • Early Growth Response Protein 3
  • Species Specificity
  • Translocation
  • Chromosome Mapping
  • MAS1
  • Syk protein, rat
  • Oncogenes
  • Nuclear Proteins
  • Cell Line, Transformed
  • Intracellular Signaling Peptides and Proteins
  • Leukaemia
  • Northern Blotting
  • SYK protein, human
  • CD Antigens
  • Southern Blotting
  • Cytochrome P-450 Enzyme System
  • Carbon-Oxygen Lyases
  • Chromosome 6
  • Egr3 protein, rat
  • Neoplastic Cell Transformation
  • MCF-7 Cells
  • DNA-Binding Proteins
  • DNA-(Apurinic or Apyrimidinic Site) Lyase
  • Nucleic Acid Hybridization
Tag cloud generated 16 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: MAS1 (cancer-related)

Villegas Gracia R, Franco Alzate C, Rendón Henao J, et al.
Frequency of monoclonal B-cell lymphocytosis in relatives of patients with chronic lymphocytic leukemia.
Colomb Med (Cali). 2016; 47(2):81-6 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Monoclonal B-cell lymphocytosis is a symptom free condition characterized by the circulation of small clonal population of B lymphocytes in peripheral blood (less than 5x10(9)/L) expressing an immunophenotype similar to chronic lymphocytic leukemia. Different studies based on big hospital series have manifested a higher risk in subjects with monoclonal B-cell lymphocytosis to progress to a chronic lymphocytic leukemia. The behavior of this hematologic entity is unknown therefore its frequency in sporadic chronic lymphocytic leukemia patient relatives was determined.
METHODS: Transversal descriptive study, 8 color flow cytometry was performed using two of the tubes of the Euro Flow recommended panel, with modifications, for the diagnose of chronic lymphoproliferative disorders of B lymphocytes; besides, a fluorescence in situ hybridization was performed. univariate and bivariate analyses of the information were performed.
RESULTS: Monoclonal B-cell lymphocytosis frequency found in 51 analyzed relatives was 2%, it was a female participant, 59 years old, with a total leukocyte count of 7.7x10(9)/L and a B lymphocyte count of 0.124x10(9)/L; from these, 0.04x10(9)/L were clonal cells with restrictions of the kappa light chain. Rearrangements of the IGH gene (14q32) were found.
CONCLUSION: Monoclonal B-cell lymphocytosis was detected in one relative of a patient with sporadic chronic lymphocytic leukemia in a frequency similar to the one reported in general population.

Yu C, Tang W, Wang Y, et al.
Downregulation of ACE2/Ang-(1-7)/Mas axis promotes breast cancer metastasis by enhancing store-operated calcium entry.
Cancer Lett. 2016; 376(2):268-77 [PubMed] Related Publications
The renin-angiotensin system (RAS) is an important component of the tumor microenvironment and plays a key role in promoting cancer cell proliferation, angiogenesis, metabolism, migration and invasion. Meanwhile, the arm of angiotensin-converting enzyme (ACE)2/angiotensin-(1-7) [Ang-(1-7)]/Mas axis in connection with RAS is associated with anti-proliferative, vasodilatory and anti-metastatic properties. Previous studies have shown that Ang-(1-7) reduces the proliferation of orthotopic human breast tumor growth by inhibiting cancer-associated fibroblasts. However, the role of ACE/Ang-(1-7)/Mas axis in the metastasis of breast cancer cells is still unknown. In the present study, we found that ACE2 protein level is negatively correlated with the metastatic ability of breast cancer cells and breast tumor grade. Upregulation of ACE2/Ang-(1-7)/Mas axis inhibits breast cancer cell migration and invasion in vivo and in vitro. Mechanistically, ACE2/Ang-(1-7)/Mas axis activation inhibits store-operated calcium entry (SOCE) and PAK1/NF-κB/Snail1 pathways, and induces E-cadherin expression. In summary, our results demonstrate that downregulation of ACE2/Ang-(1-7)/Mas axis stimulates breast cancer metastasis through the activation of SOCE and PAK1/NF-κB/Snail1 pathways. These results provide new mechanisms by which breast cancer develop metastasis and shed light on developing novel anti-metastasis therapeutics for metastatic breast cancer by modulating ACE2/Ang-(1-7)/Mas axis.

Schirmer MA, Lüske CM, Roppel S, et al.
Relevance of Sp Binding Site Polymorphism in WWOX for Treatment Outcome in Pancreatic Cancer.
J Natl Cancer Inst. 2016; 108(5) [PubMed] Free Access to Full Article Related Publications
BACKGROUND: A genome-wide association study (GWAS) suggested inherited genetic single-nucleotide polymorphisms (SNPs) affecting overall survival (OS) in advanced pancreatic cancer. To identify robust clinical biomarkers, we tested the strongest reported candidate loci in an independent patient cohort, assessed cellular drug sensitivity, and evaluated molecular effects.
METHODS: This study comprised 381 patients with histologically verified pancreatic ductal adenocarcinoma treated with gemcitabine-based chemotherapy. The primary outcome was the relationship between germline polymorphisms and OS. Functional assays addressed pharmacological dose-response effects in lymphoblastoid cell lines (LCLs) and pancreatic cancer cell lines (including upon RNAi), gene expression analyses, and allele-specific transcription factor binding. All statistical tests were two-sided.
RESULTS: The A allele (26% in Caucasians) at SNP rs11644322 in the putative tumor suppressor gene WWOX conferred worse prognosis. Median OS was 14 months (95% confidence interval [CI] = 12 to 15 months), 13 months (95% CI = 11 to 15 months), and nine months (95% CI = 7 to 12 months) for the GG, GA, and AA genotypes, respectively (P trend < .001 for trend in univariate log-rank assuming a codominant mode of inheritance; advanced disease subgroup P trend < .001). Mean OS was 25 months (95% CI = 21 to 29 months), 19 months (95% CI = 15 to 22 months), and 13 months (95% CI = 10 to 16 months), respectively. This effect held true after adjustment for age, performance status according to Eastern Cooperative Oncology Group classification, TNM, grading, and resection status and was comparable with the strongest established prognostic factors in multivariable analysis. Consistently, reduced responsiveness to gemcitabine, but not 5-fluorouracil, along with lower WWOX expression was demonstrated in LCLs harboring the AA genotype. Likewise, RNAi-mediated WWOX knockdown in pancreatic cancer cells confirmed differential cytostatic drug sensitivity. In electrophoretic mobility shift assays, the A allele exhibited weaker binding of Sp family members Sp1/Sp3.
CONCLUSIONS: WWOX rs11644322 represents a major predictive factor in gemcitabine-treated pancreatic cancer. Decreased WWOX expression may interfere with gemcitabine sensitivity, and allele-specific binding at rs11644332 might be a causative molecular mechanism behind the observed clinical associations.

Seekhuntod S, Thavarungkul P, Chaichanawongsaroj N
Validation of a Multiplex Allele-Specific Polymerase Chain Reaction Assay for Detection of KRAS Gene Mutations in Formalin-Fixed, Paraffin-Embedded Tissues from Colorectal Cancer Patients.
PLoS One. 2016; 11(1):e0147672 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Patients with KRAS mutations do not respond to epidermal growth factor receptor (EGFR) inhibitors and fail to benefit from adjuvant chemotherapy. Mutation analysis of KRAS is needed before starting treatment with monoclonal anti-EGFR antibodies in patients with metastatic colorectal cancer (mCRC). The objective of this study is to develop a multiplex allele-specific PCR (MAS-PCR) assay to detect KRAS mutations.
METHODS: We developed a single-tube MAS-PCR assay for the detection of seven KRAS mutations (G12D, G12A, G12R, G12C, G12S, G12V, and G13D). We performed MAS-PCR assay analysis for KRAS on DNA isolated from 270 formalin-fixed paraffin-embedded (FFPE) colorectal cancer tissues. Sequences of all 270 samples were determined by pyrosequencing. Seven known point-mutation DNA samples diluted with wild-type DNA were assayed to determine the limitation of detection and reproducibility of the MAS-PCR assay.
RESULTS: Overall, the results of MAS-PCR assay were in good concordance with pyrosequencing, and only seven discordant samples were found. The MAS-PCR assay reproducibly detected 1 to 2% mutant alleles. The most common mutations were G13D in codon 13 (49.17%), G12D (25.83%) and G12V (12.50%) in codon 12.
CONCLUSION: The MAS-PCR assay provides a rapid, cost-effective, and reliable diagnostic tool for accurate detection of KRAS mutations in routine FFPE colorectal cancer tissues.

Gupta SK, Kizilbash SH, Carlson BL, et al.
Delineation of MGMT Hypermethylation as a Biomarker for Veliparib-Mediated Temozolomide-Sensitizing Therapy of Glioblastoma.
J Natl Cancer Inst. 2016; 108(5) [PubMed] Article available free on PMC after 01/05/2017 Related Publications
BACKGROUND: Sensitizing effects of poly-ADP-ribose polymerase inhibitors have been studied in several preclinical models, but a clear understanding of predictive biomarkers is lacking. In this study, in vivo efficacy of veliparib combined with temozolomide (TMZ) was evaluated in a large panel of glioblastoma multiforme (GBM) patient-derived xenografts (PDX) and potential biomarkers were analyzed.
METHODS: The efficacy of TMZ alone vs TMZ/veliparib was compared in a panel of 28 GBM PDX lines grown as orthotopic xenografts (8-10 mice per group); all tests of statistical significance were two-sided. DNA damage was analyzed by γH2AX immunostaining and promoter methylation of DNA repair gene O6-methylguanine-DNA-methyltransferase (MGMT) by Clinical Laboratory Improvement Amendments-approved methylation-specific polymerase chain reaction.
RESULTS: The combination of TMZ/veliparib statistically significantly extended survival of GBM models (P < .05 by log-rank) compared with TMZ alone in five of 20 MGMT-hypermethylated lines (average extension in median survival = 87 days, range = 20-150 days), while the combination was ineffective in six MGMT-unmethylated lines. In the MGMT promoter-hypermethylated GBM12 line (median survival with TMZ+veliparib = 189 days, 95% confidence interval [CI] = 59 to 289 days, vs TMZ alone = 98 days, 95% CI = 49 to 210 days, P = .04), the profound TMZ-sensitizing effect of veliparib was lost when MGMT was overexpressed (median survival with TMZ+veliparib = 36 days, 95% CI = 28 to 38 days, vs TMZ alone = 35 days, 95% CI = 32 to 37 days, P = .87), and a similar association was observed in two nearly isogenic GBM28 sublines with an intact vs deleted MGMT locus. In comparing DNA damage signaling after dosing with veliparib/TMZ or TMZ alone, increased phosphorylation of damage-responsive proteins (KAP1, Chk1, Chk2, and H2AX) was observed only in MGMT promoter-hypermethylated lines.
CONCLUSION: Veliparib statistically significantly enhances (P < .001) the efficacy of TMZ in tumors with MGMT promoter hypermethylation. Based on these data, MGMT promoter hypermethylation is being used as an eligibility criterion for A071102 (NCT02152982), the phase II/III clinical trial evaluating TMZ/veliparib combination in patients with GBM.

Martinez E, Silvy F, Fina F, et al.
Rs488087 single nucleotide polymorphism as predictive risk factor for pancreatic cancers.
Oncotarget. 2015; 6(37):39855-64 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
Pancreatic cancer (PC) is a devastating disease progressing asymptomatically until death within months after diagnosis. Defining at-risk populations should promote its earlier diagnosis and hence also avoid its development. Considering the known involvement in pancreatic disease of exon 11 of the bile salt-dependent lipase (BSDL) gene that encodes variable number of tandem repeat (VNTR) sequences, we hypothesized upon the existence of a genetic link between predisposition to PC and mutations in VNTR loci. To test this, BSDL VNTR were amplified by touchdown-PCR performed on genomic DNA extracted from cancer tissue or blood samples from a French patient cohort and amplicons were Sanger sequenced. A robust method using probes for droplet digital (dd)-PCR was designed to discriminate the C/C major from C/T or T/T minor genotypes. We report that the c.1719C > T transition (SNP rs488087) present in BSDL VNTR may be a useful marker for defining a population at risk of developing PC (occurrence: 63.90% in the PC versus 27.30% in the control group). The odds ratio of 4.7 for the T allele was larger than those already determined for other SNPs suspected to be predictive of PC. Further studies on tumor pancreatic tissue suggested that a germline T allele may favor Kras G12R/G12D somatic mutations which represent negative prognostic factors associated with reduced survival. We propose that the detection of the T allele in rs488087 SNP should lead to an in-depth follow-up of patients in whom an association with other potential risk factors of pancreatic cancer may be present.

Li Z, Xie Y, Zhong T, et al.
Expression and clinical contribution of MRGD mRNA in non-small cell lung cancers.
J BUON. 2015 Jul-Aug; 20(4):1101-6 [PubMed] Related Publications
PURPOSE: MAS-related G protein-coupled receptor, member D (MRGD) has been reported to be involved in tumorigenesis in vivo. However, the clinical role of MRGD in non-small cell lung cancer (NSCLC) remains unclarified. The purpose of the current study was to detect the expression of MRGD mRNA in NSCLC formalin-fixed (FF), paraffin-embedded (PE) tissues and to investigate the clinicopathological significance of the MRGD level in NSCLC patients.
METHODS: The expression of MRGD mRNA was examined in 125 NSCLC tissue samples together with paired para-noncancerous FF/PE tissues by using real time quantitative PCR (qRT-PCR). Furthermore, the relationship between MRGD level and clinicopathological parameters of NSCLC was analyzed.
RESULTS: The average level of MRGD in NSCLC tumor tissues (1.0682±0.6096) was remarkably higher than that in the adjacent non-cancerous lung tissue (0.3994±0.2838, p<0.001). The area under curve (AUC) of receiver operating characteristic curve (ROC) of MRGD mRNA was 0.853 (95% CI: 0.808-0.898, p(0.001). Moreover, the level of MRGD mRNA was found to be correlated to lymph node metastasis (r=0.219, p=0.014), tumor size (r=0.221, p=0.013) and clinical TNM stage (r=0.187, p=0.037). Finally, the survival of patients in high MGRD expression group was 7.94±9.85 months, remarkably shorter than that of the low expression group (20.84±1.19 months, p=0.049).
CONCLUSIONS: MRGD may be a vital diagnostic and prognostic factor in NSCLC. MRGD possesses the potential to become a new target for the molecular therapy of NSCLC.

Collignon A, Perles-Barbacaru AT, Robert S, et al.
A pancreatic tumor-specific biomarker characterized in humans and mice as an immunogenic onco-glycoprotein is efficient in dendritic cell vaccination.
Oncotarget. 2015; 6(27):23462-79 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
Oncofetal fucose-rich glycovariants of the pathological bile salt-dependent lipase (pBSDL) appear during human pancreatic oncogenesis and are detected by themonoclonal antibody J28 (mAbJ28). We aimed to identify murine counterparts onpancreatic ductal adenocarcinoma (PDAC) cells and tissue and investigate the potential of dendritic cells (DC) loaded with this unique pancreatic tumor antigen to promote immunotherapy in preclinical trials. Pathological BSDLs purified from pancreatic juices of patients with PDAC were cleaved to generate glycosylated C-terminal moieties (C-ter) containing mAbJ28-reactive glycoepitopes. Immunoreactivity of the murine PDAC line Panc02 and tumor tissue to mAbJ28 was detected by immunohistochemistry and flow cytometry. C-ter-J28+ immunization promoted Th1-dominated immune responses. In vitro C-ter-J28+-loaded DCskewed CD3+ T-cells toward Th1 polarization. C-ter-J28+-DC-vaccinations selectively enhanced cell immunoreactivity to Panc02, as demonstrated by CD4+- and CD8+-T-cell activation, increased percentages of CD4+- and CD8+-T-cells and NK1.1+ cells expressing granzyme B, and T-cell cytotoxicity. Prophylactic and therapeutic C-ter-J28+-DC-vaccinations reduced ectopic Panc02-tumor growth, provided long-lasting protection from Panc02-tumor development in 100% of micebut not from melanoma, and attenuated progression of orthotopic tumors as revealed by MRI. Thusmurine DC loaded with pancreatic tumor-specific glycoepitope C-ter-J28+ induce efficient anticancer adaptive immunity and represent a potential adjuvant therapy for patients afflicted with PDAC.

Chevalier N, Paris F, Fontana S, et al.
Postpubertal Persistent Hyperestrogenemia in McCune-Albright Syndrome: Unilateral Oophorectomy Improved Fertility but Detected an Unexpected Borderline Epithelial Ovarian Tumor.
J Pediatr Adolesc Gynecol. 2015; 28(6):e169-72 [PubMed] Related Publications
BACKGROUND: McCune-Albright syndrome (MAS), due to a somatic mutation of the GNAS1 gene, begins usually in girls with peripheral precocious puberty. Ovarian autonomy may persist in adulthood with acyclic hyperestrogenemia, infertility, and a potential risk of estrogen-dependent cancer.
CASE: A 22-year-old woman, with MAS, was referred for infertility with left macropolycystic ovary, hyperestrogenemia, and chronic anovulation unsuccessfully treated by controlled hyperstimulation. Once ovarian cyst punctures and cDNA analysis verified that GNAS1 mutation was restricted to the left ovary, unilateral ovariectomy was performed. It improved right ovarian function, allowed an in vitro fertilization-induced pregnancy, but revealed an unexpected borderline epithelial ovarian tumor.
SUMMARY AND CONCLUSION: Several breast cancers have already been reported in young MAS patients but not a borderline epithelial ovarian tumor. In this context, we would recommend that persistent hyperestrogenemia in an adult be corrected and gynecological follow-up of the breasts, ovaries, and endometrium be implemented.

Liu Y, Li B, Wang X, et al.
Angiotensin-(1-7) Suppresses Hepatocellular Carcinoma Growth and Angiogenesis via Complex Interactions of Angiotensin II Type 1 Receptor, Angiotensin II Type 2 Receptor and Mas Receptor.
Mol Med. 2015; 21:626-36 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
We recently confirmed that angiotensin II (Ang II) type 1 receptor (AT1R) was overexpressed in hepatocellular carcinoma tissue using a murine hepatoma model. Angiotensin(Ang)-(1-7) has been found beneficial in ameliorating lung cancer and prostate cancer. Which receptor of Ang-(1-7) is activated to mediate its effects is much speculated. This study was designed to investigate the effects of Ang-(1-7) on hepatocellular carcinoma, as well as the probable mechanisms. H22 hepatoma-bearing mice were randomly divided into five groups for treatment: mock group, low-dose Ang-(1-7), high-dose Ang-(1-7), high-dose Ang-(1-7) + A779 and high-dose Ang-(1-7) + PD123319. Ang-(1-7) treatment inhibited tumor growth time- and dose-dependently by arresting tumor proliferation and promoting tumor apoptosis as well as inhibiting tumor angiogenesis. The effects of Ang-(1-7) on tumor proliferation and apoptosis were reversed by coadministration with A779 or PD123319, whereas the effects on tumor angiogenesis were completely reversed by A779 but not by PD123319. Moreover, Ang-(1-7) downregulated AT1R mRNA, upregulated mRNA levels of Ang II type 2 receptor (AT2R) and Mas receptor (MasR) and p38-MAPK phosphorylation and suppressed H22 cell-endothelial cell communication. Thus, Ang-(1-7) administration suppresses hepatocellular carcinoma via complex interactions of AT1R, AT2R and MasR and may provide a novel and promising approach for the treatment of hepatocellular carcinoma.

Srivastava J, Robertson CL, Gredler R, et al.
Astrocyte Elevated Gene-1 (AEG-1) Contributes to Non-thyroidal Illness Syndrome (NTIS) Associated with Hepatocellular Carcinoma (HCC).
J Biol Chem. 2015; 290(25):15549-58 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
Non-thyroidal illness syndrome (NTIS), characterized by low serum 3,5,3'-triiodothyronine (T3) with normal l-thyroxine (T4) levels, is associated with malignancy. Decreased activity of type I 5'-deiodinase (DIO1), which converts T4 to T3, contributes to NTIS. T3 binds to thyroid hormone receptor, which heterodimerizes with retinoid X receptor (RXR) and regulates transcription of target genes, such as DIO1. NF-κB activation by inflammatory cytokines inhibits DIO1 expression. The oncogene astrocyte elevated gene-1 (AEG-1) inhibits RXR-dependent transcription and activates NF-κB. Here, we interrogated the role of AEG-1 in NTIS in the context of hepatocellular carcinoma (HCC). T3-mediated gene regulation was analyzed in human HCC cells, with overexpression or knockdown of AEG-1, and primary hepatocytes from AEG-1 transgenic (Alb/AEG-1) and AEG-1 knock-out (AEG-1KO) mice. Serum T3 and T4 levels were checked in Alb/AEG-1 mice and human HCC patients. AEG-1 and DIO1 levels in human HCC samples were analyzed by immunohistochemistry. AEG-1 inhibited T3-mediated gene regulation in human HCC cells and mouse hepatocytes. AEG-1 overexpression repressed and AEG-1 knockdown induced DIO1 expression. An inverse correlation was observed between AEG-1 and DIO1 levels in human HCC patients. Low T3 with normal T4 was observed in the sera of HCC patients and Alb/AEG-1 mice. Inhibition of co-activator recruitment to RXR and activation of NF-κB were identified to play a role in AEG-1-mediated down-regulation of DIO1. AEG-1 thus might play a role in NTIS associated with HCC and other cancers.

Yang Q, Mas A, Diamond MP, Al-Hendy A
The Mechanism and Function of Epigenetics in Uterine Leiomyoma Development.
Reprod Sci. 2016; 23(2):163-75 [PubMed] Related Publications
Uterine leiomyomas, also known as uterine fibroids, are the most common pelvic tumors, occurring in nearly 70% of all reproductive-aged women and are the leading indication for hysterectomy worldwide. The development of uterine leiomyomas involve a complex and heterogeneous constellation of hormones, growth factors, stem cells, genetic, and epigenetic abnormalities. An increasing body of evidence emphasizes the important contribution of epigenetics in the pathogenesis of leiomyomas. Genome-wide methylation analysis demonstrates that a subset of estrogen receptor (ER) response genes exhibit abnormal hypermethylation levels that are inversely correlated with their RNA expression. Several tumor suppressor genes, including Kruppel-like factor 11 (KLF11), deleted in lung and esophageal cancer 1 (DLEC1), keratin 19 (KRT19), and death-associated protein kinase 1 (DAPK1) also display higher hypermethylation levels in leiomyomas when compared to adjacent normal tissues. The important role of active DNA demethylation was recently identified with regard to the ten-eleven translocation protein 1 and ten-eleven translocation protein 3-mediated elevated levels of 5-hydroxymethylcytosine in leiomyoma. In addition, both histone deacetylase and histone methyltransferase are reported to be involved in the biology of leiomyomas. A number of deregulated microRNAs have been identified in leiomyomas, leading to an altered expression of their targets. More recently, the existence of side population (SP) cells with characteristics of tumor-initiating cells have been characterized in leiomyomas. These SP cells exhibit a tumorigenic capacity in immunodeficient mice when exposed to 17β-estradiol and progesterone, giving rise to fibroid-like tissue in vivo. These new findings will likely enhance our understanding of the crucial role epigenetics plays in the pathogenesis of uterine leiomyomas as well as point the way to novel therapeutic options.

Fonseca J, Adriana C, Fróis-Borges M, et al.
Ostomy metastasis after pull endoscopic gastrostomy: a unique favorable outcome.
Nutr Hosp. 2015; 31(4):1879-81 [PubMed] Related Publications
Head and neck cancer (HNC) patients tend to develop dysphagia. In order to preserve the nutritional support, many undergo endoscopic gastrostomy (PEG). In HNC patients, ostomy metastasis is considered a rare complication of PEG, but there are no reports of successful treatment of these metastatic cancers. We report the case of a 65 years old pharyngeal/laryngeal cancer patient who underwent a PEG before the neck surgery. He was considered to be cured, resumed oral intake and the PEG tube was removed. Ten months after, he returned with a metastasis at the ostomy site. A block resection of the stomach and abdominal wall was performed. Two years after the abdominal surgery, he is free of disease. Although usually considered a rare complication of the endoscopic gastrostomy, ostomy metastasis may be more frequent than usually considered and the present case report demonstrates that these patients may have a favourable outcome.

Zheng S, Yang Y, Song R, et al.
Ang-(1-7) promotes the migration and invasion of human renal cell carcinoma cells via Mas-mediated AKT signaling pathway.
Biochem Biophys Res Commun. 2015; 460(2):333-40 [PubMed] Related Publications
Ang-(1-7) is an active peptide component of renin-angiotensin system and endogenous ligand for Mas receptor. In the current study, we showed that Ang-(1-7) enhanced migratory and invasive abilities of renal cell carcinoma cells 786-O and Caki-1 by wound-healing, transwell migration and transwell invasion assays. Mas antagonist A779 pretreatment or shRNA-mediated Mas knockdown abolished the stimulatory effect of Ang-(1-7). Furthermore, Ang-(1-7)-stimulated AKT activation was inhibited by either A779 pretreatment or Mas knockdown. Blockage of AKT signaling by AKT inhibitor VIII inhibited Ang-(1-7)-induced migration and invasion in 786-O cells. Taken together, our results provided the first evidence for the pro-metastatic role of Ang-(1-7) in RCC, which may help to better understand the molecular mechanism underlying the progression of this tumor.

Chen W, Zhang S, Zhang W, et al.
Elevated serum adenosine deaminase levels in secondary hemophagocytic lymphohistiocytosis.
Int J Lab Hematol. 2015; 37(4):544-50 [PubMed] Related Publications
INTRODUCTION: Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory condition caused by activated T cells and macrophages. Adenosine deaminase (ADA) plays an important role in immune regulation, especially in the proliferation, maturation, and differentiation of lymphocytes. Its role has been studied in inflammation and malignancy. Here, we present for the first time the alteration of ADA in secondary HLH (sHLH).
METHODS: Serum ADA levels were measured in 20 cases with lymphoma-associated hemophagocytic syndrome (LAHS), 15 with infection-associated hemophagocytic syndrome (IAHS), six with macrophage activation syndrome (MAS) as experimental group. Additionally, we enrolled 20 cases with lymphoma, 15 with infection, six with autoimmunity who were all not associated with HLH as conditional control group and 20 healthy subjects as blank group. We also demonstrated the ADA levels in 20 LAHS cases and 21 benign disease-associated HLH cases (IAHS and MAS).
RESULTS: Serum ADA levels were significantly higher in patients with LAHS, IAHS, and MAS compared to the healthy subjects (P < 0.001) and conditional control group (P < 0.05). Serum ADA levels of patients with LAHS were significantly higher than benign disease-associated HLH cases (P < 0.05). The optimum ADA cutoff point for LAHS was 89.25 U/L, with a sensitivity and specificity of 85.0% and 76.2%, respectively.
CONCLUSION: Serum ADA levels were increased in sHLH suggesting a partial role of activated T-cell response in the disease pathophysiology. Serum ADA levels were particularly higher in LAHS and probably be a potential indicator of underlying lymphoma in sHLH patients.

Chen R, Ravindra VM, Cohen AL, et al.
Molecular features assisting in diagnosis, surgery, and treatment decision making in low-grade gliomas.
Neurosurg Focus. 2015; 38(3):E2 [PubMed] Related Publications
The preferred management of suspected low-grade gliomas (LGGs) has been disputed, and the implications of molecular changes for medical and surgical management of LGGs are important to consider. Current strategies that make use of molecular markers and imaging techniques and therapeutic considerations offer additional options for management of LGGs. Mutations in the isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) genes suggest a role for this abnormal metabolic pathway in the pathogenesis and progression of these primary brain tumors. Use of magnetic resonance spectroscopy can provide preoperative detection of IDH-mutated gliomas and affect surgical planning. In addition, IDH1 and IDH2 mutation status may have an effect on surgical resectability of gliomas. The IDH-mutated tumors exhibit better prognosis throughout every grade of glioma, and mutation may be an early genetic event, preceding lineage-specific secondary and tertiary alterations that transform LGGs into secondary glioblastomas. The O6-methylguanine-DNAmethyltransferase (MGMT) promoter methylation and 1p19q codeletion status can predict sensitivity to chemotherapy and radiation in low- and intermediate-grade gliomas. Thus, these recent advances, which have led to a better understanding of how molecular, genetic, and epigenetic alterations influence the pathogenicity of the different histological grades of gliomas, can lead to better prognostication and may lead to specific targeted surgical interventions and medical therapies.

Liu B, Liu Y, Jiang Y
Podocalyxin promotes glioblastoma multiforme cell invasion and proliferation by inhibiting angiotensin-(1-7)/Mas signaling.
Oncol Rep. 2015; 33(5):2583-91 [PubMed] Related Publications
Podocalyxin (PODX) reportedly enhances invasion in many human cancers including glioblastoma multiforme (GBM). Recent studies have shown that the local renin-angiotensin system (RAS) in tumor environment contributes significantly to tumor progression. As a counter-regulatory axis in RAS, angiotensin (Ang)-(1-7)/Mas signaling has been shown to inhibit the growth and invasiveness of several human cancers including GBM. In the present study, we examined the crosstalk between PODX and Ang-(1-7)/Mas signaling in GBM cells, and assessed its impact on GBM cell invasion and proliferation. A strong negative correlation between the expression of PODX and Mas in GBM tumor tissues from 10 consecutive patients (r=-0.768, p<0.01) was observed. The stable overexpression of PODX in LN-229 and U-118 MG human GBM cells decreased the expression of Mas at the mRNA and protein levels, which led to decreased density of Ang-(1-7)-binding Mas on the cell membrane. This effect was completely abolished by selective phosphatidylinositol 3-kinase (PI3K) inhibitor BKM120. By contrast, the stable knockdown of PODX in LN-229 and U-118 MG cells increased the expression of Mas and the density of Ang-(1-7)-binding Mas on the cell membrane. Overexpression and knockdown of PODX respectively reversed and enhanced the inhibitory effects of Ang-(1-7) on the expression/activity of matrix metalloproteinase-9 and cell invasion and proliferation in GBM cells. Although the overexpression of Mas showed no significant effect on the promoting effect of PODX on GBM cell invasion and proliferation in the absence of Ang-(1-7), it completely eliminated the effect of PODX in the presence of Ang-(1-7). In conclusion, to the best of our knowledge, the present study provided the first evidence that PODX inhibits Ang-(1-7)/Mas signaling by downregulating the expression of Mas through a PI3K-dependent mechanism in GBM cells. This effect led to enhanced GBM cell invasion and proliferation. The results of this study add new insight into the biological functions of PODX and the molecular mechanisms underlying GBM progression.

Mas A, Cervelló I, Fernández-Álvarez A, et al.
Overexpression of the truncated form of High Mobility Group A proteins (HMGA2) in human myometrial cells induces leiomyoma-like tissue formation.
Mol Hum Reprod. 2015; 21(4):330-8 [PubMed] Related Publications
The pathogenesis of uterine leiomyomas, the most common benign tumor in women, is still unknown. This lack of basic knowledge limits the development of novel non-invasive therapies. Our group has previously demonstrated that leiomyoma side population (SP) cells are present in tumor lesions and act like putative tumor-initiating stem cells in human leiomyoma. Moreover, accumulated evidence demonstrates that these benign tumors of mesenchymal origin are characterized by rearrangements of the High Mobility Group A proteins (HMGA). In this work, we tested the hypothesis that leiomyoma development may be due to overexpression of HMGA2 (encoding high mobility group AT-hook2) in myometrial stem cells using in vitro and in vivo approaches. Our work demonstrates that the truncated/short form of HMGA2 induces myometrial cell transformation toward putative tumor-initiating leiomyoma cells and opens up new possibilities to understand the origin of leiomyomas and the development of new therapeutic approaches.

Liu JB, Dai CM, Su XY, et al.
Gene microarray assessment of multiple genes and signal pathways involved in androgen-dependent prostate cancer becoming androgen independent.
Asian Pac J Cancer Prev. 2014; 15(22):9791-5 [PubMed] Related Publications
To study the gene expression change and possible signal pathway during androgen-dependent prostate cancer (ADPC) becoming androgen-independent prostate cancer (AIPC), an LNCaP cell model of AIPC was established using flutamide in combination with androgen-free environment inducement, and differential expression genes were screened by microarray. Then the biological process, molecular function and KEGG pathway of differential expression genes are analyzed by Molecule Annotation System (MAS). By comparison of 12,207 expression genes, 347 expression genes were acquired, of which 156 were up-ragulated and 191 down-regulated. After analyzing the biological process and molecule function of differential expression genes, these genes are found to play crucial roles in cell proliferation, differntiation, cell cycle control, protein metabolism and modification and other biological process, serve as signal molecules, enzymes, peptide hormones, cytokines, cytoskeletal proteins and adhesion molecules. The analysis of KEGG show that the relevant genes of AIPC transformation participate in glutathione metabolism, cell cycle, P53 signal pathway, cytochrome P450 metabolism, Hedgehog signal pathway, MAPK signal pathway, adipocytokines signal pathway, PPAR signal pathway, TGF-β signal pathway and JAK-STAT signal pathway. In conclusion, during the process of ADPC becoming AIPC, it is not only one specific gene or pathway, but multiple genes and pathways that change. The findings above lay the foundation for study of AIPC mechanism and development of AIPC targeting drugs.

Li Y, Wang J, Li X, et al.
Role of the Wilms' tumor 1 gene in the aberrant biological behavior of leukemic cells and the related mechanisms.
Oncol Rep. 2014; 32(6):2680-6 [PubMed] Related Publications
The Wilms' tumor 1 (WT1) gene is one of the regulating factors in cell proliferation and development. It is a double-functional gene: an oncogene and a tumor suppressor. This gene was found to be highly expressed in many leukemic cell lines and in patients with acute myeloid leukemia. In the present study, we demonstrated that the WT1 gene was commonly expressed in leukemic cell lines apart from U937 cells. The K562 cell line which expresses WT1 at a high level (mRNA and protein) was used in the entire experiment. By MTT and colony formation assays, we found that curcumin, an inhibitor of the WT1 protein, inhibited cell proliferation and clonogenicity in a time- and dose-dependent manner. It also caused cell cycle arrest at the G2/M phase. We then designed specific short hairpin RNAs (shRNAs) which could downregulate WT1 by 70-80% at the mRNA and protein levels. Reduction in the WT1 levels attenuated the proliferative ability and clonogenicity. Cell cycle progression analysis indicated that the proportion of cells in the G0/G1 phase increased while the proportion in the S phase decreased distinctively. ChIP-DNA selection and ligation (DSL) experiment identified a cohort of genes whose promoters are targeted by WT1. These genes were classified into different cellular signaling pathways using MAS software and included the Wnt/β-catenin pathway, MAPK signaling pathway, apoptosis pathway, and the cell cycle. We focused on the Wnt/β-catenin signaling pathway, and compared expression of several genes in the K562 cells transfected with the control shRNA and WT1-specific shRNA. β-catenin, an important gene in the Wnt canonical pathway, was downregulated after WT1 RNAi. Target genes of β-catenin which participate in cell proliferation and cell cycle regulation, such as CCND1 and MYC, were also significantly downregulated. Collectively, these data suggest that WT1 functions as an oncogene in leukemia cells, and one important mechanism is regulation of the Wnt/β-catenin pathway.

Ouaïssi M, Silvy F, Loncle C, et al.
Further characterization of HDAC and SIRT gene expression patterns in pancreatic cancer and their relation to disease outcome.
PLoS One. 2014; 9(9):e108520 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
Ductal adenocarcinoma of the pancreas is ranking 4 for patient' death from malignant disease in Western countries, with no satisfactory treatment. We re-examined more precisely the histone deacetylases (HDAC) and Sirtuin (SIRT) gene expression patterns in pancreatic cancer with more pancreatic tumors and normal tissues. We also examined the possible relationship between HDAC gene expression levels and long term disease outcome. Moreover, we have evaluated by using an in vitro model system of human pancreatic tumor cell line whether HDAC7 knockdown may affect the cell behavior. We analyzed 29 pancreatic adenocarcinoma (PA), 9 chronic pancreatitis (CP), 8 benign pancreatic (BP) and 11 normal pancreatic tissues. Concerning pancreatic adenocarcinoma, we were able to collect biopsies at the tumor periphery. To assess the possible involvement of HDAC7 in cell proliferation capacity, we have generated recombinant human Panc-1 tumor which underexpressed or overexpressed HDAC7. The expression of HDAC1,2,3,4,7 and Nur77 increased in PA samples at levels significantly higher than those observed in the CP group (p = 0.0160; 0.0114; 0.0227; 0.0440; 0.0136; 0.0004, respectively). The expression of HDAC7, was significantly greater in the PA compared with BP tissue samples (p = 0.05). Mean mRNA transcription levels of PA for HDAC7 and HDAC2 were higher when compared to their counterpart biopsies taken at the tumor periphery (p = 0.0346, 0.0053, respectively). Moreover, the data obtained using confocal microscopy and a quantitative method of immunofluorescence staining strongly support the HDAC7 overexpression in PA surgical specimens. The number of deaths and recurrences at the end of follow up were significantly greater in patients with overexpression of HDAC7. Interestingly, the rate of growth was significantly reduced in the case of cell carrying shRNA construct targeting HDAC7 encoding gene when compared to the parental Panc-1 tumor cells (p = 0.0015) at 48 h and 96 h (p = 0.0021). This study strongly support the notion that HDAC7play a role in pancreatic adenocarcinoma progression.

Alband N, Korbonits M
Familial pituitary tumors.
Handb Clin Neurol. 2014; 124:339-60 [PubMed] Related Publications
Pituitary adenomas are benign intracranial neoplasms that present a major clinical concern due to hormone overproduction and/or tumor mass effects. The majority of pituitary adenomas occur sporadically; however, familial cases are increasingly being recognized, such as multiple endocrine neoplasia type 1 (MEN1), Carney complex (CNC), and familial isolated pituitary adenoma (FIPA). Familial pituitary tumors appear to differ from their sporadic counterparts both in their genetic basis and in clinical characteristics. Evidence suggests that, especially in MEN1 and FIPA, tumors are more aggressive and affect patients at a younger age, therefore justifying the importance of early diagnosis, while in Carney complex pituitary hyperplasia is common. The genetic alterations responsible for the formation of familial pituitary syndromes include the MEN1 gene, responsible for about 80% of MEN1 cases, the regulatory subunit of the protein kinase A, PRKAR1A, responsible for about 70% of Carney complex cases, and AIP, the gene coding the aryl hydrocarbon receptor interacting protein, responsible for about 20% of FIPA cases. Rarely other genes have also been found responsible for familial pituitary adenoma cases. McCune-Albright syndrome (MAS) also has a genetic origin due to mosaic mutations in the G protein-coupled α subunit coded by the GNAS1 gene. In this chapter, we summarize the genetic and clinical characteristics of these familial pituitary syndromes and MAS.

Wang AS, Lodi A, Rivera LB, et al.
HR-MAS MRS of the pancreas reveals reduced lipid and elevated lactate and taurine associated with early pancreatic cancer.
NMR Biomed. 2014; 27(11):1361-70 [PubMed] Related Publications
The prognosis for patients with pancreatic cancer is extremely poor, as evidenced by the disease's five-year survival rate of ~5%. New approaches are therefore urgently needed to improve detection, treatment, and monitoring of pancreatic cancer. MRS-detectable metabolic changes provide useful biomarkers for tumor detection and response-monitoring in other cancers. The goal of this study was to identify MRS-detectable biomarkers of pancreatic cancer that could enhance currently available imaging approaches. We used (1) H high-resolution magic angle spinning MRS to probe metabolite levels in pancreatic tissue samples from mouse models and patients. In mice, the levels of lipids dropped significantly in pancreata with lipopolysaccharide-induced inflammation, in pancreata with pre-cancerous metaplasia (4 week old p48-Cre;LSL-Kras(G12D) mice), and in pancreata with pancreatic intraepithelial neoplasia, which precedes invasive pancreatic cancer (8 week old p48-Cre LSL-Kras(G12D) mice), to 26 ± 19% (p = 0.03), 19 ± 16% (p = 0.04), and 26 ± 10% (p = 0.05) of controls, respectively. Lactate and taurine remained unchanged in inflammation and in pre-cancerous metaplasia but increased significantly in pancreatic intraepithelial neoplasia to 266 ± 61% (p = 0.0001) and 999 ± 174% (p < 0.00001) of controls, respectively. Importantly, analysis of patient biopsies was consistent with the mouse findings. Lipids dropped in pancreatitis and in invasive cancer biopsies to 29 ± 15% (p = 0.01) and 26 ± 38% (p = 0.02) of normal tissue. In addition, lactate and taurine levels remained unchanged in inflammation but rose in tumor samples to 244 ± 155% (p = 0.02) and 188 ± 67% (p = 0.02), respectively, compared with normal tissue. Based on these findings, we propose that a drop in lipid levels could serve to inform on pancreatitis and cancer-associated inflammation, whereas elevated lactate and taurine could serve to identify the presence of pancreatic intraepithelial neoplasia and invasive tumor. Our findings may help enhance current imaging methods to improve early pancreatic cancer detection and monitoring.

Zhao SD, Parmigiani G, Huttenhower C, Waldron L
Más-o-menos: a simple sign averaging method for discrimination in genomic data analysis.
Bioinformatics. 2014; 30(21):3062-9 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
MOTIVATION: The successful translation of genomic signatures into clinical settings relies on good discrimination between patient subgroups. Many sophisticated algorithms have been proposed in the statistics and machine learning literature, but in practice simpler algorithms are often used. However, few simple algorithms have been formally described or systematically investigated.
RESULTS: We give a precise definition of a popular simple method we refer to as más-o-menos, which calculates prognostic scores for discrimination by summing standardized predictors, weighted by the signs of their marginal associations with the outcome. We study its behavior theoretically, in simulations and in an extensive analysis of 27 independent gene expression studies of bladder, breast and ovarian cancer, altogether totaling 3833 patients with survival outcomes. We find that despite its simplicity, más-o-menos can achieve good discrimination performance. It performs no worse, and sometimes better, than popular and much more CPU-intensive methods for discrimination, including lasso and ridge regression.
AVAILABILITY AND IMPLEMENTATION: Más-o-menos is implemented for survival analysis as an option in the survHD package, available from and submitted to Bioconductor.

Sueur C, Lupo J, Mas P, et al.
Difference in cytokine production and cell cycle progression induced by Epstein-Barr virus Lmp1 deletion variants in Kmh2, a Hodgkin lymphoma cell line.
Virol J. 2014; 11:94 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
BACKGROUND: Epstein-Barr virus (EBV) is associated with 20-40% of Hodgkin's Lymphoma (HL) cases. EBV-encoded latent membrane protein 1 (LMP1) is a well-known oncogenic protein and two C-terminal deletion variants, del30-LMP1 and del69-LMP1, have been described in animal models to be more tumorigenic than the wild-type form. This work aims to detail the implication of LMP1 in the development of HL and to characterize the particular effects of these variants.
METHODS: We established HL-derived cell lines stably transfected with the pRT-LMP1 vector coding for the EBNA1 gene and allowing expression of the different LMP1 variants under the control of a doxycyclin-inducible promoter. Communication between cells was assessed by measuring the expression of various pro-inflammatory cytokines by flow cytometry after intracellular LMP1 and cytokine double staining. Proliferative properties of LMP1 variants were also compared by studying the repartition of cells in the different phases of the cell cycle after EdU incorporation combined to LMP1 and DAPI staining.
RESULTS: All LMP1 proteins induced the expression of several pro-inflammatory cytokines such as TNF-α, TNF-β, IL-6, RANTES/CCL5 and IFN-γ. However, the del30-LMP1 variant induced cytokine expression at a lower level than the other variants, especially IFN-γ, while the del69-LMP1 variant stimulated greater cytokine expression. In addition, we measured that all LMP1 proteins greatly impacted the cell cycle progression, triggering a reduction in the number of cells in S-phase and an accumulation of cells in the G2/M phase compared to the HL-non induced cells. Interestingly, the del30-LMP1 variant reduced the number of cells in S-phase in a significantly greater manner and also increased the number of cells in the G0/G1 phase of the cell cycle.
CONCLUSION: Weak IFN-γ expression and specific alteration of the cell cycle might be a way for del30-LMP1 infected cells to escape the immune anti-viral response and to promote the development of cancer. The differences observed between the LMP1 variants reflect their own oncogenic properties and eventually impact the development of HL.

Correira Pereira MA, Santos CA, Almeida Brito J, Fonseca J
Scored Patient-Generated Subjective Global Assessment, albumin and transferrin for nutritional assessment of gastrostomy fed head or neck cancer patients.
Nutr Hosp. 2014; 29(2):420-6 [PubMed] Related Publications
INTRODUCTION: Gastrostomy fed head or neck cancer patients frequently have impaired speech capacities. Enteral feeding teams frequently depend on laboratorial or anthropometrical parameters for nutritional assessment.
AIMS: In these patients, this study aimed to evaluate: (1) the practicability of Scored - Patient-Generated Subjective Global Assessment (PG-SGA); (2) their nutritional status using the Scored-PG-SGA; (3) association of serum albumin and transferrin values to the nutritional status rating using PG-SGA.
METHODS: On adult outpatients with head or neck cancer under prolonged (> 1 month) gastrostomy feeding, Scored-PGSGA, albumin and transferrin were evaluated during the same appointment.
RESULTS: Scored-PG-SGA was easily feasible in 42 patients, even in patients with speech difficulties. Twenty-five patients were moderately/severely undernourished (PG-SGA/B+C). Scored-PG-SGA rated 41 patients as ≥ 2, thus needing nutritional/ pharmacologic intervention. Albumin was low in 13 patients. Transferrin was low in 19 patients. Average albumin and transferrin in moderately/severely undernourished patients (PG-SGA/B+C) was significantly lower than in well-nourished (PG-SGA/A). There was association between Scored- PG-SGA rating, albumin and transferrin.
CONCLUSIONS: In PEG fed head or neck cancer patients, PGSGA was practicable and useful, even in patients with impaired speaking skills. Most patients displayed moderate/severe malnutrition (PG-SGA/B+C). Scored-PG-SGA rated 41 patients as needing for nutritional/pharmacological intervention. Scored-PG-SGA should be systematically included in the evaluation of these patients. In these patients, albumin and transferrin levels showed relation with Scored-PG-SGA and should be considered as nutritional biomarkers.

Laviolette LA, Hodgkinson KM, Minhas N, et al.
17β-estradiol upregulates GREB1 and accelerates ovarian tumor progression in vivo.
Int J Cancer. 2014; 135(5):1072-84 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
Exogenous 17β-estradiol (E2) accelerates the progression of ovarian cancer in the transgenic tgCAG-LS-TAg mouse model of the disease. We hypothesized that E2 has direct effects on ovarian cancer cells and this study was designed to determine the molecular mechanisms by which E2 accelerates ovarian tumor progression. Mouse ovarian cancer ascites (MAS) cell lines were derived from tgCAG-LS-TAg mice. Following intraperitoneal engraftment of two MAS cell lines, MASC1 and MASE2, into SCID mice, exogenous E2 significantly decreased the survival time and increased the tumor burden. Microarray analysis performed on MASE2-derived tumors treated with E2 or placebo showed that E2 treatment caused the upregulation of 197 genes and the downregulation of 55 genes. The expression of gene regulated by estrogen in breast cancer 1 (Greb1) was upregulated in mouse tumors treated with E2 and was overexpressed in human ovarian cancers relative to human ovarian surface epithelium, suggesting a role for GREB1 in human ovarian tumor progression. RNA interference-mediated knockdown of GREB1 in MASE2 cells decreased their proliferation rate in vitro and increased survival time in mice engrafted with the cells. These results emphasize the importance of E2 in ovarian tumor progression and identify Greb1 as a novel gene target for therapeutic intervention.

Grinde MT, Skrbo N, Moestue SA, et al.
Interplay of choline metabolites and genes in patient-derived breast cancer xenografts.
Breast Cancer Res. 2014; 16(1):R5 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
INTRODUCTION: Dysregulated choline metabolism is a well-known feature of breast cancer, but the underlying mechanisms are not fully understood. In this study, the metabolomic and transcriptomic characteristics of a large panel of human breast cancer xenograft models were mapped, with focus on choline metabolism.
METHODS: Tumor specimens from 34 patient-derived xenograft models were collected and divided in two. One part was examined using high-resolution magic angle spinning (HR-MAS) MR spectroscopy while another part was analyzed using gene expression microarrays. Expression data of genes encoding proteins in the choline metabolism pathway were analyzed and correlated to the levels of choline (Cho), phosphocholine (PCho) and glycerophosphocholine (GPC) using Pearson's correlation analysis. For comparison purposes, metabolic and gene expression data were collected from human breast tumors belonging to corresponding molecular subgroups.
RESULTS: Most of the xenograft models were classified as basal-like (N = 19) or luminal B (N = 7). These two subgroups showed significantly different choline metabolic and gene expression profiles. The luminal B xenografts were characterized by a high PCho/GPC ratio while the basal-like xenografts were characterized by highly variable PCho/GPC ratio. Also, Cho, PCho and GPC levels were correlated to expression of several genes encoding proteins in the choline metabolism pathway, including choline kinase alpha (CHKA) and glycerophosphodiester phosphodiesterase domain containing 5 (GDPD5). These characteristics were similar to those found in human tumor samples.
CONCLUSION: The higher PCho/GPC ratio found in luminal B compared with most basal-like breast cancer xenograft models and human tissue samples do not correspond to results observed from in vitro studies. It is likely that microenvironmental factors play a role in the in vivo regulation of choline metabolism. Cho, PCho and GPC were correlated to different choline pathway-encoding genes in luminal B compared with basal-like xenografts, suggesting that regulation of choline metabolism may vary between different breast cancer subgroups. The concordance between the metabolic and gene expression profiles from xenograft models with breast cancer tissue samples from patients indicates that these xenografts are representative models of human breast cancer and represent relevant models to study tumor metabolism in vivo.

Dadone B, Ambrosetti D, Carpentier X, et al.
A renal metanephric adenoma showing both a 2p16e24 deletion and BRAF V600E mutation: a synergistic role for a tumor suppressor gene on chromosome 2p and BRAF activation?
Cancer Genet. 2013 Sep-Oct; 206(9-10):347-52 [PubMed] Related Publications
Metanephric adenomas (MAs) are rare benign tumors that may be difficult to recognize. Specific genetic anomalies might aid in diagnosis, but genomic data are limited and conflicting. Consistent mutations of the BRAF gene have been recently reported in MAs and could become useful as a discriminative marker among renal tumors. We report here a case of MA, showing both a BRAF V600E mutation and a segmental loss within bands 2p16 and 2p24 as the sole quantitative genomic anomaly. We compared the borders and size of the deleted region in our case to those of five cases of MAs previously reported. We identified a common minimal region containing 87 genes, among which several tumor suppressor genes could be candidate actors in the pathogenesis of MA. We ruled out MSH2 and MSH6 as target gene candidates, both located in the deleted region, on the basis of preserved expression and microsatellite sequence stability. Our study confirms the recurrence of a BRAF mutation and of 2p alterations in MAs. This first case showing simultaneous presence of a BRAF mutation and a 2p deletion raises the question of a synergistic role for these two anomalies in the pathogenesis of MAs.

Blaise BJ, Lopez C, Vercherat C, et al.
Metabolic expressivity of human genetic variants: NMR metabotyping of MEN1 pathogenic mutants.
J Pharm Biomed Anal. 2014; 93:118-24 [PubMed] Related Publications
Functional consequences of mutations in predisposition genes for familial cancer syndromes remain often elusive, especially when the corresponding gene products play pleiotropic functions and interact with numerous partners. Understanding the consequences of these genetic alterations requires access to their functional effects at the phenotypic level. Nuclear magnetic resonance (NMR) has emerged as a promising functional genomics probe, through its ability to monitor the consequences of genetic variations at the biochemical level. Here, we determine by NMR the metabolic perturbations associated with different disease-related mutations in the MEN1 gene, responsible for the multiple endocrine neoplasia syndrome, type 1 (MEN1), an example of hereditary cancer. The MEN1 gene encodes the Menin protein. Based on a cellular model that allows exogenous overexpression of either the wild type (WT) Menin protein or disease-related variant forms, we evaluate the feasibility of using metabolic profiles to discriminate cells with WT versus variant Menin overexpression. High-resolution magic angle spinning (HRMAS) NMR of whole cells allows to determine the metabolic features associated with overexpression of WT Menin as compared to the one of six different missense variants observed in MEN1 patients. We then identify several statistically significant individual metabolites associated with the metabolic signature of pathogenic versus WT variants. Whether such a metabolic phenotyping approach using cell lines could be exploited as a functional test in a human genetic cancer syndrome is further discussed.

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