Exploring the Gain of Function Contribution of AKT to Mammary Tumorigenesis in Mouse Models

Elevated expression of AKT has been noted in a significant percentage of primary human breast cancers, mainly as a consequence of the PTEN/PI3K pathway deregulation. To investigate the mechanistic basis of the AKT gain of function-dependent mechanisms of breast tumorigenesis, we explored the phenotype induced by activated AKT transgenes in a quantitative manner. We generated several transgenic mice lines expressing different levels of constitutively active AKT in the mammary gland. We thoroughly analyzed the preneoplastic and neoplastic mammary lesions of these mice and correlated the process of tumorigenesis to AKT levels. Finally, we analyzed the impact that a possible senescent checkpoint might have in the tumor promotion inhibition observed, crossing these lines to mammary specific p53(R172H) mutant expression, and to p27 knock-out mice. We analyzed the benign, premalignant and malignant lesions extensively by pathology and at molecular level analysing the expression of proteins involved in the PI3K/AKT pathway and in cellular senescence. Our findings revealed an increased preneoplastic phenotype depending upon AKT signaling which was not altered by p27 or p53 loss. However, p53 inactivation by R172H point mutation combined with myrAKT transgenic expression significantly increased the percentage and size of mammary carcinoma observed, but was not sufficient to promote full penetrance of the tumorigenic phenotype. Molecular analysis suggest that tumors from double myrAKT;p53(R172H) mice result from acceleration of initiated p53(R172H) tumors and not from bypass of AKT-induced oncogenic senescence. Our work suggests that tumors are not the consequence of the bypass of senescence in MIN. We also show that AKT-induced oncogenic senescence is dependent of pRb but not of p53. Finally, our work also suggests that the cooperation observed between mutant p53 and activated AKT is due to AKT-induced acceleration of mutant p53-induced tumors. Finally, our work shows that levels of activated AKT are not essential in the induction of benign or premalignant tumors, or in the cooperation of AKT with other tumorigenic signal such as mutant p53, once AKT pathway is activated, the relative level of activity seems not to determine the phenotype

Association between dynamic asymmetry of the newborn's head and intrauterine factors Associação entre a assimetria dinâmica da cabeça do recém-nascido e fatores intra-uterinos

A non-comparable, individual, observational and contemporary cross-sectional study in newborns was made to determine the dynamic lateralization in the head turning after release from the midline and its relationship with obstetric variables. From October to December of 2005, 320 newborns were admitted to the Adjacent Lodgings of the University Hospital of Santa Maria. From those, 89 were selected for assessment of the vestibular function since they have had previously fetal static control through ultrasound. Our results show that the right-sided head lateralization was significantly greater than the left-sided. The predominancy of the lateralization towards the right side also occurred in cephalic presentations and left-sided back, however these were not significant. Results corroborate with the existing literature and suggest an association between fetal static and vestibular function.<br>Com o objetivo determinar a lateralização dinâmica na prova da queda da cabeça e sua associação com variáveis obstétricas, foi realizado um estudo transversal no recém-nascido, não comparado, individual, observacional e contemporâneo. No período de outubro a dezembro de 2005, 320 recém-nascidos foram admitidos no Alojamento Conjunto do Hospital Universitário de Santa Maria, e destes 89 foram selecionados para avaliação da função vestibular, por terem feito controle da estática fetal através do ultrasom. Nossos resultados mostram que a lateralização da cabeça para a direita foi significativamente maior do que para esquerda. Também este predomínio da lateralização para a direita ocorreu nas apresentações cefálicas e com o dorso para esquerda, no entanto estes não foram significativos. Nossos resultados corroboram com a literatura existente, e sugerem uma associação entre a estática fetal e a função vestibular