Akt1 and akt2 play distinct roles in the initiation and metastatic phases of mammary tumor progression.
The phosphatidylinositol 3-kinase (PI3K)/Akt survival pathway is often dysregulated in cancer. Our previous studies have shown that coexpression of activated Akt1 with activated ErbB2 or polyoma virus middle T antigen uncoupled from the PI3K pathway (PyVmT Y315/322F) accelerates mammary tumor development but cannot rescue the metastatic phenotype associated with these models. Here, we report the generation of transgenic mice expressing activated Akt2 in the mammary epithelium. Like the mouse mammary tumor virus-Akt1 strain, mammary-specific expression of Akt2 delayed mammary gland involution. However, in contrast to Akt1, coexpression of Akt2 with activated ErbB2 or PyVmT Y315/322F in the mammary glands of transgenic mice did not affect the latency of tumor development. Strikingly, Akt2 coexpresssion markedly increased the incidence of pulmonary metastases in both tumor models, demonstrating a unique role in tumor progression. Together, these observations argue that these highly conserved kinases have distinct biological and biochemical outputs that play opposing roles in mammary tumor induction and metastasis.
Dillon
Rachelle L
RL
Goodman Cancer Centre and Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
Marcotte
Richard
R
Hennessy
Bryan T
BT
Woodgett
James R
JR
Mills
Gordon B
GB
Muller
William J
WJ
D000818:Animals; D018450:Disease Progression; D007150:Immunohistochemistry; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology / Q000473:pathology*; D008324:Mammary Tumor Virus, Mouse / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt