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Amplification of TRIM44: pairing a prognostic target with potential therapeutic strategy.

التفاصيل البيبلوغرافية
العنوان: Amplification of TRIM44: pairing a prognostic target with potential therapeutic strategy.
المؤلفون: Ong CA; Affiliations of authors: MRC Cancer Unit, Cambridge, UK (C-AJO, CSR-I, MO, CEW, AN, RCF); Cancer Research UK Cambridge Institute, Cambridge, UK (NBS, OMR, D-eH, MIK, CC, KB); UK Cambridge Esophagogastric Centre, Addenbrooke's Hospital, Cambridge, UK (RHH)., Shannon NB; Affiliations of authors: MRC Cancer Unit, Cambridge, UK (C-AJO, CSR-I, MO, CEW, AN, RCF); Cancer Research UK Cambridge Institute, Cambridge, UK (NBS, OMR, D-eH, MIK, CC, KB); UK Cambridge Esophagogastric Centre, Addenbrooke's Hospital, Cambridge, UK (RHH)., Ross-Innes CS; Affiliations of authors: MRC Cancer Unit, Cambridge, UK (C-AJO, CSR-I, MO, CEW, AN, RCF); Cancer Research UK Cambridge Institute, Cambridge, UK (NBS, OMR, D-eH, MIK, CC, KB); UK Cambridge Esophagogastric Centre, Addenbrooke's Hospital, Cambridge, UK (RHH)., O'Donovan M; Affiliations of authors: MRC Cancer Unit, Cambridge, UK (C-AJO, CSR-I, MO, CEW, AN, RCF); Cancer Research UK Cambridge Institute, Cambridge, UK (NBS, OMR, D-eH, MIK, CC, KB); UK Cambridge Esophagogastric Centre, Addenbrooke's Hospital, Cambridge, UK (RHH)., Rueda OM; Affiliations of authors: MRC Cancer Unit, Cambridge, UK (C-AJO, CSR-I, MO, CEW, AN, RCF); Cancer Research UK Cambridge Institute, Cambridge, UK (NBS, OMR, D-eH, MIK, CC, KB); UK Cambridge Esophagogastric Centre, Addenbrooke's Hospital, Cambridge, UK (RHH)., Hu DE; Affiliations of authors: MRC Cancer Unit, Cambridge, UK (C-AJO, CSR-I, MO, CEW, AN, RCF); Cancer Research UK Cambridge Institute, Cambridge, UK (NBS, OMR, D-eH, MIK, CC, KB); UK Cambridge Esophagogastric Centre, Addenbrooke's Hospital, Cambridge, UK (RHH)., Kettunen MI; Affiliations of authors: MRC Cancer Unit, Cambridge, UK (C-AJO, CSR-I, MO, CEW, AN, RCF); Cancer Research UK Cambridge Institute, Cambridge, UK (NBS, OMR, D-eH, MIK, CC, KB); UK Cambridge Esophagogastric Centre, Addenbrooke's Hospital, Cambridge, UK (RHH)., Walker CE; Affiliations of authors: MRC Cancer Unit, Cambridge, UK (C-AJO, CSR-I, MO, CEW, AN, RCF); Cancer Research UK Cambridge Institute, Cambridge, UK (NBS, OMR, D-eH, MIK, CC, KB); UK Cambridge Esophagogastric Centre, Addenbrooke's Hospital, Cambridge, UK (RHH)., Noorani A; Affiliations of authors: MRC Cancer Unit, Cambridge, UK (C-AJO, CSR-I, MO, CEW, AN, RCF); Cancer Research UK Cambridge Institute, Cambridge, UK (NBS, OMR, D-eH, MIK, CC, KB); UK Cambridge Esophagogastric Centre, Addenbrooke's Hospital, Cambridge, UK (RHH)., Hardwick RH; Affiliations of authors: MRC Cancer Unit, Cambridge, UK (C-AJO, CSR-I, MO, CEW, AN, RCF); Cancer Research UK Cambridge Institute, Cambridge, UK (NBS, OMR, D-eH, MIK, CC, KB); UK Cambridge Esophagogastric Centre, Addenbrooke's Hospital, Cambridge, UK (RHH)., Caldas C; Affiliations of authors: MRC Cancer Unit, Cambridge, UK (C-AJO, CSR-I, MO, CEW, AN, RCF); Cancer Research UK Cambridge Institute, Cambridge, UK (NBS, OMR, D-eH, MIK, CC, KB); UK Cambridge Esophagogastric Centre, Addenbrooke's Hospital, Cambridge, UK (RHH)., Brindle K; Affiliations of authors: MRC Cancer Unit, Cambridge, UK (C-AJO, CSR-I, MO, CEW, AN, RCF); Cancer Research UK Cambridge Institute, Cambridge, UK (NBS, OMR, D-eH, MIK, CC, KB); UK Cambridge Esophagogastric Centre, Addenbrooke's Hospital, Cambridge, UK (RHH)., Fitzgerald RC; Affiliations of authors: MRC Cancer Unit, Cambridge, UK (C-AJO, CSR-I, MO, CEW, AN, RCF); Cancer Research UK Cambridge Institute, Cambridge, UK (NBS, OMR, D-eH, MIK, CC, KB); UK Cambridge Esophagogastric Centre, Addenbrooke's Hospital, Cambridge, UK (RHH). rcf29@hutchison-mrc.ac.uk.
المصدر: Journal of the National Cancer Institute [J Natl Cancer Inst] 2014 Apr 28; Vol. 106 (5). Date of Electronic Publication: 2014 Apr 28.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Oxford University Press Country of Publication: United States NLM ID: 7503089 Publication Model: Electronic Cited Medium: Internet ISSN: 1460-2105 (Electronic) Linking ISSN: 00278874 NLM ISO Abbreviation: J Natl Cancer Inst Subsets: MEDLINE
أسماء مطبوعة: Publication: <2003-> : Cary, NC : Oxford University Press
Original Publication: Bethesda, Md., U. S. Dept. of Health, Education, and Welfare, Public Health Service, National Institutes of Health; Washington, for sale by the Supt. of Docs., U. S. Govt. Print. Off.
مواضيع طبية MeSH: Carrier Proteins/*genetics , Neoplasms/*drug therapy , Neoplasms/*genetics, Animals ; Biomarkers, Tumor/genetics ; Breast Neoplasms/drug therapy ; Breast Neoplasms/genetics ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Carrier Proteins/biosynthesis ; Esophageal Neoplasms/drug therapy ; Esophageal Neoplasms/genetics ; Esophageal Neoplasms/metabolism ; Esophageal Neoplasms/pathology ; Female ; Gene Amplification ; Gene Knockdown Techniques ; Heterografts ; Humans ; Intracellular Signaling Peptides and Proteins ; Male ; Mice ; Mice, Inbred BALB C ; Molecular Targeted Therapy ; Neoplasm Staging ; Neoplasms/metabolism ; Neoplasms/pathology ; Phosphoinositide-3 Kinase Inhibitors ; Signal Transduction ; Stomach Neoplasms/drug therapy ; Stomach Neoplasms/genetics ; Stomach Neoplasms/metabolism ; Stomach Neoplasms/pathology ; TOR Serine-Threonine Kinases/antagonists & inhibitors ; TOR Serine-Threonine Kinases/metabolism ; Tripartite Motif Proteins
مستخلص: Background: Many prognostic biomarkers have been proposed recently. However, there is a lack of therapeutic strategies exploiting novel prognostic biomarkers. We aimed to propose therapeutic options in patients with overexpression of TRIM44, a recently identified prognostic gene.
Methods: Genomic and transcriptomic data of epithelial cancers (n = 1932), breast cancers (BCs; n = 1980) and esophago-gastric cancers (EGCs; n = 163) were used to identify genomic aberrations driving TRIM44 overexpression. The driver gene status of TRIM44 was determined using a small interfering RNA (siRNA) screen of the 11p13 amplicon. Integrative analysis was applied across multiple datasets to identify pathway activation and potential therapeutic strategies. Validation of the in silico findings were performed using in vitro assays, xenografts, and patient samples (n = 160).
Results: TRIM44 overexpression results from genomic amplification in 16.1% of epithelial cancers, including 8.1% of EGCs and 6.1% of BCs. This was confirmed using fluorescent in situ hybridization. The siRNA screen confirmed TRIM44 to be a driver of the amplicon. In silico analysis revealed an association between TRIM44 and mTOR signalling, supported by a decrease in mTOR signalling after siRNA knockdown of TRIM44 in cell lines and colocalization of TRIM44 and p-mTOR in patient samples. In vitro inhibition studies using an mTOR inhibitor (everolimus) decreased cell viability in two TRIM44-amplified cells lines by 88% and 70% compared with 35% in the control cell line. These findings were recapitulated in xenograft models.
Conclusions: Genomic amplification drives TRIM44 overexpression in EGCs and BCs. Targeting the mTOR pathway provides a potential therapeutic option for TRIM44-amplified tumors.
(© The Author 2014. Published by Oxford University Press.)
التعليقات: Comment in: J Natl Cancer Inst. 2014 Apr 28;106(5):. (PMID: 24777109)
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معلومات مُعتمدة: MC_EX_MR/K00316X/1 United Kingdom MRC_ Medical Research Council; NIHR-RP-02-12-011 United Kingdom DH_ Department of Health; 16942 United Kingdom CRUK_ Cancer Research UK; 17242 United Kingdom CRUK_ Cancer Research UK; MC_EX_UU_MR/K00316X/1 United Kingdom MRC_ Medical Research Council; MC_U105365007 United Kingdom MRC_ Medical Research Council; MC_UU_12022/2 United Kingdom MRC_ Medical Research Council
المشرفين على المادة: 0 (Biomarkers, Tumor)
0 (Carrier Proteins)
0 (Intracellular Signaling Peptides and Proteins)
0 (Phosphoinositide-3 Kinase Inhibitors)
0 (TRIM44 protein, human)
0 (Tripartite Motif Proteins)
EC 2.7.1.1 (MTOR protein, human)
EC 2.7.11.1 (TOR Serine-Threonine Kinases)
تواريخ الأحداث: Date Created: 20140430 Date Completed: 20140708 Latest Revision: 20240210
رمز التحديث: 20240210
مُعرف محوري في PubMed: PMC4112924
DOI: 10.1093/jnci/dju050
PMID: 24777112
قاعدة البيانات: MEDLINE
الوصف
تدمد:1460-2105
DOI:10.1093/jnci/dju050