title: Role of the tripartite motif protein 27 in cancer development.
abstract: BACKGROUND
  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 β-galactosidase [SA-β-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, χ(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-β-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-β-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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Section of Cancer Biology, University College London Cancer Institute, University College London, 72 Huntley St, London WC1E 6DD, UK. g.zoumpoulidou@cancer.ucl.ac.uk
authors.forename: Georgia
authors.initials: G
authors.lastname: Zoumpoulidou
authors.forename: Cristina
authors.initials: C
authors.lastname: Broceño
authors.forename: He
authors.initials: H
authors.lastname: Li
authors.forename: Demelza
authors.initials: D
authors.lastname: Bird
authors.forename: George
authors.initials: G
authors.lastname: Thomas
authors.forename: Sibylle
authors.initials: S
authors.lastname: Mittnacht
mesh_terms: D049109:Cell Proliferation; D016922:Cellular Senescence; D015986:Confounding Factors, Epidemiologic; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D005347:Fibroblasts / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D018075:RNA, Complementary / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D012107:Research Design; D016160:Retinoblastoma Protein / Q000172:deficiency / Q000378:metabolism; D012878:Skin Neoplasms / Q000139:chemically induced / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases; D015854:Up-Regulation; D000070584:Tripartite Motif Proteins
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D018075:RNA, Complementary; D016160:Retinoblastoma Protein; D044767:Ubiquitin-Protein Ligases; C064419:TRIM27 protein, human; D000070584:Tripartite Motif Proteins; C489296:Trim27 protein, mouse