RESUMEN
Germline mutations in RAD51C predispose to breast and ovarian cancers. However, the mechanism of RAD51C-mediated carcinogenesis is poorly understood. We previously reported a first-generation Rad51c-knock-out mouse model, in which a spontaneous loss of both Rad51c and Trp53 together resulted in a high incidence of sebaceous carcinomas, particularly in preputial glands. Here we describe a second-generation mouse model, in which Rad51c is deleted, alone or together with Trp53, in sebaceous glands, using Cre-mediated recombination. We demonstrate that deletion of Rad51c alone is not sufficient to drive tumourigenesis and may only cause keratinization of preputial sebocytes. However, deletion of Rad51c together with Trp53 leads to tumour development at around 6 months of age, compared to 11 months for single Trp53-mutant mice. Preputial glands of double-mutant mice are also characterized by increased levels of cell proliferation and DNA damage and form multiple hyperplasias, detectable as early as 2 months of age. Our results reveal a critical synergy between Rad51c and Trp53 in tumour progression and provide a predictable in vivo model system for studying mechanisms of Rad51c-mediated carcinogenesis.
Asunto(s)
Carcinogénesis/genética , Transformación Celular Neoplásica/genética , Mutación/genética , Recombinasa Rad51/genética , Glándulas Sebáceas/patología , Proteína p53 Supresora de Tumor/genética , Animales , Proteínas de Unión al ADN , Femenino , Ratones , Ratones Noqueados , Ratones Transgénicos , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Glándulas Sebáceas/metabolismoRESUMEN
Multiple observations suggest a cell type-specific role for TP53 in mammary epithelia. We developed an in vitro assay, in which primary mouse mammary epithelial cells (mMECs) progressed from lumenal to basal-like phenotypes based on expression of Krt18 or ΔNp63, respectively. Such transition was markedly delayed in Trp53(-/-) mMECs suggesting that Trp53 is required for specification of the basal, but not lumenal cells. Evidence from human basal-like cell lines suggests that TP53 may support the activity of ΔNp63 by preventing its translocation from nucleoplasm into nucleoli. In human lumenal cells, activation of TP53 by inhibiting MDM2 or BRCA1 restored the nucleoplasmic expression of ΔNp63. Trp53(-/-) mMECs eventually lost epithelial features resulting in upregulation of MDM2 and translocation of ΔNp63 into nucleoli. We propose that TP63 may contribute to TP53-mediated oncogenic transformation of epithelial cells and shed light on tissue- and cell type-specific biases observed for TP53-related cancers.