Distinct Biological Roles for the Akt Family in Mammary Tumor Progression

Abstract

The phosphatidylinositol 3′ kinase/Akt pathway is frequently dysregulated in cancer, which can have unfavorable consequences in terms of cell proliferation, survival, metabolism, and migration. Increasing evidence suggests that Akt1, Akt2, and Akt3 play unique roles in breast cancer initiation and progression. We have recently shown that in contrast to Akt1, which accelerates mammary tumor induction in transgenic mice, Akt2 promotes metastasis of tumor cells without affecting the latency of tumor development. Despite the distinct phenotypic outputs resulting from Akt1 or Akt2 activation, very little is known about the mode by which such unique functions originate from these highly related kinases. Here we discuss potential mechanisms contributing to the differing functional specificity of Akt1 and Akt2 with respect to migration, invasion, and metastasis.

Knockdown of CABYR-a/b Increases Chemosensitivity of Human Non–Small Cell Lung Cancer Cells through Inactivation of Akt

“…Because the Akt pathway is known to be essential for cell proliferation and survival and its activity is constitutive in NSCLC cells (14)(15)(16)20), we focused on this pathway in this study. Akt requires phosphorylation at 2 specific amino acid residues, namely threonine 308 and serine 473; phosphatidylinositol-dependent kinase 1 (PDK1) phosphorylates threonine 308, and the mTOR complex-2 (mTORC2) phosphorylates serine 473 (21). Because reactivity with phospho-specific Akt antibodies correlates strongly with in vitro kinase activity and A549 does not exhibit Thr308 phosphorylation under normal culture conditions (20), only the phosphorylation of Akt at Ser473 was examined in this study.…”

Genomically amplified Akt3 activates DNA repair pathway and promotes glioma progression

“…Although they appear to be very similar proteins, developmental studies as well as assessment of the isoforms in cancer models have revealed that they possess distinct functions (1,8). The most extensive work on isoform differences has been performed in breast cancer.…”

Akt2 expression is associated with good long-term prognosis in oestrogen receptor positive breast cancer

“…The molecular mechanisms that lead to the different functions of Akt isoforms are unclear. It has been suggested that the specific functions of Akt1 and Akt2 are regulated through distinct subcellular localization (4). Akt2 has been shown to be primarily expressed in the stroma of the mammary gland (2).…”

“…This indicates not only that the different isoforms may have different functions, but also that the same isoform can take both protective and destructive roles possibly depending on the stage of breast cancer development. Studies on the potential different roles of the Akt isoforms have been reviewed (4). Activated Akt (pAkt) has been associated with up to 40 % of breast cancers (5).…”

“…Activated Akt (pAkt) has been associated with up to 40 % of breast cancers (5). The mechanisms behind enhanced Akt phosphorylation are several, including HER2 amplification, PI3K mutation and PTEN loss (4). Most results suggest that pAkt correlates with poor prognosis (6,7) and is associated with other aggressive prognostic factors, such as HER2-positivity and lymph node positive breast cancer (8).…”