Abstract
Ample evidence to date links the phosphatidylinositol 3-kinase-regulated protein kinase Akt with the induction and progression of human cancer, including breast cancer. However, there are three Akt isoforms with limited information about their specificity during oncogenesis. This study addresses the role of the three isoforms in polyoma middle T (PyMT) and ErbB2/Neu-driven mammary adenocarcinomas in mice. The effects of ablation of Akt1, Akt2, and Akt3 on the induction and the biology of these tumors were dramatically different, with ablation of Akt1 inhibiting, ablation of Akt2 accelerating, and ablation of Akt3 having a small, not statistically significant, inhibitory effect on tumor induction by both transgenes. Whereas PyMT-induced tumors are all invasive, Akt1(-/-)Neu-induced tumors are more invasive than Akt2(-/-)Neu-induced tumors. Invasiveness, however, does not always correlate with metastasis. Ablation of individual Akt isoforms does not affect the development of the mammary gland during puberty or the expression of the transgenes. Akt ablation, therefore, influences tumor induction by modulating transgene-induced oncogenic signaling. Immunostaining for Ki-67 and cyclin D1 and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assays on tissue sections revealed that the delay of tumor induction in Akt1 knockout mice is due to the inhibitory effects of Akt1 ablation on cell proliferation and survival. Given that these animal models exhibit significant similarities to human breast cancer, 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.
Highlights
ErbB2/Neu is a member of the epidermal growth factor (EGF) receptor family that is overexpressed in approximately one-third of all the cases of human breast cancer
Before addressing the role of individual Akt isoforms in mammary oncogenesis, we wanted to determine their relative expression in the mammary gland
To address the role of the three Akt isoforms in mammary oncogenesis, we crossed the Neu and the polyoma middle T (PyMT) transgenes into the Akt1À/À, Akt2À/À, and Akt3À/À genetic backgrounds
Summary
ErbB2/Neu is a member of the epidermal growth factor (EGF) receptor family that is overexpressed in approximately one-third of all the cases of human breast cancer. Overexpression of Neu activates multiple signaling pathways and is associated with poor prognosis [1]. One of the pathways activated by Neu is the phosphatidylinositol 3-kinase (PI3K)/Akt pathway [2]. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Doi:10.1158/0008-5472.CAN-06-3782 pathway is activated by polyoma middle T (PyMT), a viral oncogene [3]. Expression of either Neu or PyMT in the mammary gland of transgenic mice from mouse mammary tumor virus long terminal repeat (MMTV LTR)–driven transgenes causes mammary adenocarcinomas [4, 5]
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