Zoumpoulidou G.,University College London |
Zoumpoulidou G.,Formerly of the Institute of Cancer Research |
Broceno C.,Formerly of the Institute of Cancer Research |
Broceno C.,CIBER ISCIII |
And 8 more authors.
Journal of the National Cancer Institute | Year: 2012
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.MethodsWe 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 -/- Background s 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.ResultsTRIM27 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).ConclusionTRIM27 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. © 2012 The Author.