Akt1 and Akt2 Play Distinct Roles in the Initiation and Metastatic Phases of Mammary Tumor Progression

Abstract

The PI3K/Akt survival pathway is often dysregulated in cancer. Our previous studies have demonstrated 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 MMTV-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 impact 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.

Akt2 interacts with Snail1 in the E-cadherin promoter

“…However, in some cells its downregulation decreases the formation of metastasis (Ericson et al, 2010). On the other hand, Akt2 is required for EMT as it is activated during this transition and its downregulation prevents the acquisition of the mesenchymal phenotype or the formation of metastasis (Irie et al, 2005;Cheng et al, 2007;Rychahou et al, 2008;Dillon et al, 2009;Iliopoulos et al, 2009;Ericson et al, 2010). However, these effects are cell-dependent as in some cells Akt2 depletion by itself does not promote any effect but prevents the EMT induced by Akt1 depletion.…”

Disruption of epithelial architecture caused by loss of PTEN or by oncogenic mutant p110α/PIK3CA but not by HER2 or mutant AKT1

“…These effects are mediated through a large and diverse group of proteins that can bind selectively to the PtdInsP 3 lipid, the best studied of which are the AKT kinases [2]. It appears that the deregulation of cell growth and survival downstream of mutated PI3K/PTEN is important in mammary tumour development, mediated in large part through the Akt kinases, particularly Akt1 [16][17][18][19]. However, it also appears that the loss of cell polarity and tissue architecture can itself be an important driver of some breast tumours, rather than just a by-product of unchecked proliferation [20][21][22][23].…”

Oncogenes and Tumor Suppressor Genes

“…Direct evidence supporting a role for AKT1 in mammary tumor progression came from studies using transgenic mice that expressed different activated forms of AKT1. Expression of these in the mammary epithelium, although incapable of inducing mammary tumors, resulted in a profound involution defect (Ackler et al 2002;Dillon et al 2009;Hutchinson et al 2004). However, coexpression of an activated AKT1 mutant (AKT1-DD) with an activated ErbB2mutant (NDL) or a PI3K defective middle T oncogene resulted in a decrease in tumor latency in these tumor models (Dillon et al 2009;Hutchinson et al 2004).…”

“…Expression of these in the mammary epithelium, although incapable of inducing mammary tumors, resulted in a profound involution defect (Ackler et al 2002;Dillon et al 2009;Hutchinson et al 2004). However, coexpression of an activated AKT1 mutant (AKT1-DD) with an activated ErbB2mutant (NDL) or a PI3K defective middle T oncogene resulted in a decrease in tumor latency in these tumor models (Dillon et al 2009;Hutchinson et al 2004). AKT1 coexpression decreased lung metastases, however, in tumor-bearing animals in the MMTV ErbB2 model (Dillon et al 2009;Hutchinson et al 2004).…”

“…However, coexpression of an activated AKT1 mutant (AKT1-DD) with an activated ErbB2mutant (NDL) or a PI3K defective middle T oncogene resulted in a decrease in tumor latency in these tumor models (Dillon et al 2009;Hutchinson et al 2004). AKT1 coexpression decreased lung metastases, however, in tumor-bearing animals in the MMTV ErbB2 model (Dillon et al 2009;Hutchinson et al 2004). Conversely, germ-line deletion of AKT1 profoundly reduced mammary tumor formation in this ErbB2 mouse model of human breast cancer (Ju et al 2007;Maroulakou et al 2007).…”