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Étude des fonctions biologiques et oncosuppressives du gène de prédisposition aux Néoplasies Endocriniennes Multiples de type 1 dans les tissus hormono-dépendants chez la souris

Abstract : Mutations of the MEN1 gene predispose to multiple endocrine neoplasia type 1 (MEN1) syndrome, characterized by the occurrence of multiple endocrine tumours. Heterozygous Men1 mutant mice not only recapitulate MEN1 pathology, but also display prostatic and mammary carcinomas with a low incidence. I showed that the expression of menin, coded by the Men1 gene, was completely inactivated in the prostatic carcinomas developed in these mice. Deregulated expression of androgen receptor and the inactivation of p27 CDK inhibitor, a menin target gene, were also found in these lesions. In addition, my data demonstrated that mammary-specific disruption of the Men1 gene in mice led to high incidence of mammary intraepithelial neoplasia (MIN) from 9 months of age in the mutant mice. An unexpected leakage activity of the WapCre transgene in pituitary resulted in the development of prolactinomas and premature death in the mutant mice. Several analyses provided evidence showing that the increased incidence of MIN lesions could not be simply explained by the influence of prolactinomas. Interestingly, we observed a strong reduction of beta-catenin, a known menin partner, and E-cadherin membrane expression in these lesions, suggesting an alteration of cellular adhesion in the absence of menin. On the whole, these data indicate a potential implication of Men1 disruption in the development of prostate carcinomas and mammary intraepithelial neoplasia in mice
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Christelle Seigne. Étude des fonctions biologiques et oncosuppressives du gène de prédisposition aux Néoplasies Endocriniennes Multiples de type 1 dans les tissus hormono-dépendants chez la souris. Médecine humaine et pathologie. Université Claude Bernard - Lyon I, 2009. Français. ⟨NNT : 2009LYO10247⟩. ⟨tel-00877511⟩

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