RESUMEN
Recent studies of human cancers and mutant mouse models have implicated the Nkx3.1 homeobox gene as having a key role in prostate carcinogenesis. Consistent with such a role, here we show that Nkx3.1 displays growth-suppressing activities in cell culture, and that aged Nkx3.1 mutant mice display histopathological defects resembling prostatic intraepithelial neoplasia (PIN), the presumed precursor of human prostate cancer. Using a tissue recombination approach, we found that PIN-like lesions from Nkx3.1 mutants can undergo progressively severe histopathological alterations after serial transplantation in nude mice. Our findings indicate that Nkx3.1 loss-of-function is a critical event in prostate cancer initiation, and that Nkx3.1 mutant mice accurately model early stages of prostate carcinogenesis. More generally, our tissue recombination assay provides an empirical test to examine the relationship of PIN to prostate carcinoma.
Asunto(s)
Proteínas de Homeodominio/genética , Neoplasia Intraepitelial Prostática/genética , Neoplasias de la Próstata/genética , Factores de Transcripción/genética , Animales , División Celular/genética , División Celular/fisiología , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Silenciador del Gen , Genes Supresores de Tumor , Predisposición Genética a la Enfermedad , Proteínas de Homeodominio/fisiología , Endogamia , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Ratones Desnudos , Mutación , Neoplasia Intraepitelial Prostática/patología , Neoplasias de la Próstata/patología , Factores de Transcripción/fisiologíaRESUMEN
Mouse models have provided significant insights into the molecular mechanisms of tumor suppressor gene function. Here we use mouse models of prostate carcinogenesis to demonstrate that the Nkx3.1 homeobox gene undergoes epigenetic inactivation through loss of protein expression. Loss of function of Nkx3.1 in mice cooperates with loss of function of the Pten tumor suppressor gene in cancer progression. This cooperativity results in the synergistic activation of Akt (protein kinase B), a key modulator of cell growth and survival. Our findings underscore the significance of interactions between tissue-specific regulators such as Nkx3.1 and broad-spectrum tumor suppressors such as Pten in contributing to the distinct phenotypes of different cancers.