Regulation of Oncogenesis by Akt-Specific Isoforms

Tufts Medical Center
posted on 01/07/2009

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Tufts Medical Center Categories:
diseases:cancer
screening:assay
screening:target

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Expression of the polyoma middle T antigen (PyMT) or the HER2/Neu oncogene in the mammary gland of transgenic mice from MMTV LTR-driven expression constructs, gives rise to mammary adenocarcinomas. Here we show that ablation of Akt1 inhibits, while ablation of Akt2 accelerates tumor induction by both transgenes. The tumors arising in mice lacking individual Akt isoforms exhibit distinct histologic phenotypes. Although all these tumors are locally invasive however, they differ in metastatic potential, with the Akt1.sup.-/- tumors being less metastatic. The development of the mammary gland during puberty and the expression of MMTV LTR-driven transgenes in Akt1, Akt2 and Akt3 knockout mice are normal. These data combined, indicate that ablation of individual Akt isoforms influences tumor induction by modulating oncogenic signaling induced by the two transgenes. Further studies revealed that the delay of tumor induction in Akt1 knockout mice is due to the inhibitory affects of Akt1 ablation on cell proliferation and cell survival. The results of the present study may have significant translational implications because they may influence how Akt inhibitors will be used in the treatment of human cancer.