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dc.contributor.authorZoumpoulidou, G
dc.contributor.authorBroceno, C
dc.contributor.authorLi, H
dc.contributor.authorBird, D
dc.contributor.authorThomas, G
dc.contributor.authorMittnacht, S
dc.date.accessioned2018-08-08T10:18:11Z
dc.date.issued2012-06
dc.identifier12
dc.identifier.citationJOURNAL OF THE NATIONAL CANCER INSTITUTE, 2012, 104 pp. 941 - 952
dc.identifier.issn0027-8874
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/2301
dc.identifier.doi10.1093/jnci/djs224
dc.description.abstractBackground The tripartite motif family protein 27 (TRIM27) is a transcriptional repressor that interacts with, and attenuates senescence induction by, the retinoblastoma-associated protein (RB1). High expression of TRIM27 was noted in several human cancer types including breast and endometrial cancer, where elevated TRIM27 expression predicts poor prognosis. Here, we investigated the role of TRIM27 expression in cancer development. Methods We assessed TRIM27 expression in human cancer using cancer profiling arrays containing paired tumor and normal cRNA (n=261) as well as in murine skin cancer induced by 7, 12-dimethylbenzanthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA). We generated mice with disrupted expression of murine TRIM27 (Trim27(-/-)) and assessed their susceptibility to DMBA/TPA-induced skin tumor development compared with isogenic littermates (n=26 mice per group). We assessed the effect of Trim27 loss on senescence propensity in mouse embryonic fibroblasts (MEFs) by quantifying cell proliferation alongside senescence markers (senescence-associated beta-galactosidase [SA-beta-gal] activity and hypertrophic cell morphology). The contribution of RB1 on senescence and cancer susceptibility (n>20 mice per group) in Trim27(-/-) backgrounds was also assessed. Data were analyzed using the Student’s t, chi(2), or log-rank test as indicated. All statistical tests were two-sided. Results TRIM27 transcript levels are statistically significantly increased in common human cancers, including colon and lung, vs normal tissues (TRIM27 expression relative to ubiquitin: cancers vs normal tissues, mean=0.59, 95% confidence interval [CI]=0.55 to 0.63 vs mean=0.46, 95% CI=0.43 to 0.49, P<.001) as well as in chemically induced mouse skin cancer compared with matched normal tissue (Trim27 expression relative to Gapdh control: tumor vs normal skin, mean=4.2, 95% CI=3.97 to 4.43 vs mean=0.96, 95% CI=0.69 to 1.2, P<.001). Trim27(-/-) mice (n=14) were resistant to chemically induced skin cancer development (eight [57.2%] of 14 mice were tumor free) compared with Trim27(+/+) wild-type littermates (n=13) (one [7.7%] of 13 mice was tumor free). Trim27(-/-) MEFs show enhanced senescence propensity in response to replicative (percentage of SA-beta-gal-positive cells: Trim27(+/+) MEFs vs Trim27(-/-) MEFs, mean=14.2%, 95% CI=11.1% to 17.4% vs mean=53.3%, 95% CI=48.7% to 57.9%, P<.001) or oncogenic stress (percentage of SA-beta-gal-positive cells: Trim27(+/+) MEFs + Ras vs Trim27(-/-) MEFs + Ras, mean=24.0%, 95% CI=19.9% to 28.1% vs mean=37.3%, 95% CI=32.2% to 42.4%, P<.05) compared with Trim27(+/+) MEFs. These responses were alleviated following inactivation of murine RB1 (Rb1). Furthermore, Trim27(-/-) mice are not protected from cancers arising as a consequence of Rb1 deletion (median survival: Trim27(-/-)Rb(+/-) vs Trim27(-/-) Rb+/-, 14 vs 13 months; difference=1.0 month, 95% CI=0.5 to 1.6 months, P=.14). Conclusion TRIM27 expression is a modifier of disease incidence and progression relevant to the development of common human cancers and is a potential target for intervention in cancer. J Natl Cancer Inst 2012;104:9412-952
dc.format.extent941 - 952
dc.languageeng
dc.language.isoeng
dc.publisherOXFORD UNIV PRESS INC
dc.titleRole of the Tripartite Motif Protein 27 in Cancer Development
dc.typeJournal Article
rioxxterms.versionofrecord10.1093/jnci/djs224
rioxxterms.licenseref.startdate2012-06
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfJOURNAL OF THE NATIONAL CANCER INSTITUTE
pubs.notesaffiliation: Zoumpoulidou, G (Reprint Author), UCL, Inst Canc, Sect Canc Biol, 72 Huntley St, London WC1E 6DD, England. Zoumpoulidou, Georgia; Mittnacht, Sibylle, UCL, Inst Canc, Sect Canc Biol, London WC1E 6DD, England. Zoumpoulidou, Georgia; Broceno, Cristina; Li, He; Bird, Demelza; Thomas, George; Mittnacht, Sibylle, Inst Canc Res, Chester Beatty Labs, Sect Cell & Mol Biol, London SW3 6JB, England. Broceno, Cristina, Technol Transfer CIBER Resp Dis CIBERES, Barcelona, Spain. Li, He, UCL, Inst Ophthalmol, London WC1E 6DD, England. Thomas, George, Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA. keywords-plus: RET FINGER PROTEIN; CELLULAR SENESCENCE; TRIM PROTEINS; TUMOR-SUPPRESSOR; MOUSE; CELLS; RAS; CARCINOGENESIS; EXPRESSION; HALLMARKS research-areas: Oncology web-of-science-categories: Oncology author-email: [email protected] [email protected] funding-acknowledgement: Cancer Research UK [C107/A3096, C107/A10437, C107/10433]; Worldwide Cancer Research [12-1280] funding-text: The work reported was supported by grants from Cancer Research UK (C107/A3096, C107/A10437, and C107/10433). number-of-cited-references: 50 times-cited: 14 usage-count-last-180-days: 0 usage-count-since-2013: 11 journal-iso: J. Natl. Cancer Inst. doc-delivery-number: 969PL unique-id: ISI:000306067700011 oa: gold_or_bronze da: 2018-08-08
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams/Anti Oncogene
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams/Anti Oncogene
pubs.volume104
pubs.embargo.termsNot known
icr.researchteamAnti Oncogeneen_US
dc.contributor.icrauthorMittnacht, Sibylleen


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