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E2F1 loss induces spontaneous tumour development in Rb-deficient epidermis

Abstract

The specific ablation of Rb1 gene in epidermis (RbF/F;K14cre) promotes proliferation and altered differentiation but does not produce spontaneous tumour development. These phenotypic changes are associated with increased expression of E2F members and E2F-dependent transcriptional activity. Here, we have focused on the possible dependence on E2F1 gene function. We have generated mice that lack Rb1 in epidermis in an inducible manner (RbF/F;K14creERTM). These mice are indistinguishable from those lacking pRb in this tissue in a constitutive manner (RbF/F;K14cre). In an E2F1-null background (RbF/F;K14creERTM; and E2F1−/− mice), the phenotype due to acute Rb1 loss is not ameliorated by E2F1 loss, but rather exacerbated, indicating that pRb functions in epidermis do not rely solely on E2F1. On the other hand, RbF/F;K14creERTM;E2F1−/− mice develop spontaneous epidermal tumours of hair follicle origin with high incidence. These tumours, which retain a functional p19arf/p53 axis, also show aberrant activation of β-catenin/Wnt pathway. Gene expression studies revealed that these tumours display relevant similarities with specific human tumours. These data demonstrate that the Rb/E2F1 axis exerts essential functions not only in maintaining epidermal homoeostasis, but also in suppressing tumour development in epidermis, and that the disruption of this pathway may induce tumour progression through specific alteration of developmental programs.

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Acknowledgements

Ministerio de Ciencia e Innovación (MICINN) grants SAF2006–0121, SAF2011–26122-C02–01 and JCI-2010–06167, Comunidad Autónoma de Madrid Oncocycle Program Grant S2006/BIO-0232 and: CAM P2010/BMD-2470, Ministerio de Sanidad y Consumo grant ISCIII-RETIC RD06/0020/0029 and from Fundación Sandra Ibarra to JMP. The excellent technical support by Pilar Hernández in histology and the personnel of the CIEMAT Animal Facility are specially acknowledged.

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Correspondence to J M Paramio.

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Costa, C., Santos, M., Martínez-Fernández, M. et al. E2F1 loss induces spontaneous tumour development in Rb-deficient epidermis. Oncogene 32, 2937–2951 (2013). https://doi.org/10.1038/onc.2012.316

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