Amplification and overexpression of theAKT2 oncogene in a subset of human pancreatic ductal adenocarcinomas

Abstract

AKT2, an oncogene encoding a protein serine-threonine kinase implicated in phosphatidylinositol-3-OH kinase signaling, is amplified in some human ovarian and pancreatic carcinomas. We previously demonstrated that the tumorigenicity and invasiveness of pancreatic ductal adenocarcinoma (PDAC) cell lines with amplified AKT2 could be markedly reduced by transfection with antisense AKT2 constructs. To evaluate further the extent of AKT2 alterations in PDAC, DNA and immunohistochemical analyses were performed to assess amplification or overexpression of AKT2, respectively, in 72 PDACs. Thirty-five PDACs were subjected to Southern analyses, and AKT2 amplification was detected in seven tumors (20%). Forty-one formalin-fixed PDAC specimens were examined immunohistochemically with an anti-AKT2 monoclonal antibody, and moderate to intense staining was observed in eight tumors (20%). AKT2 immunostaining paralleled AKT2 genomic status in each of four cases in which both Southern and immunohistochemical analyses were performed. No obvious relationship was observed between AKT2 status and tumor TNM stage or grade. These observations suggest the utility of immunohistochemical analysis in assessing alterations of AKT2 in human cancers. Furthermore, the role played by the AKT2 kinase in the signaling pathways of various mitogenic growth factors implicated in the development of pancreatic cancer suggests that alteration of AKT2 may be an important component in the pathogenesis of a substantial subset of PDACs.

AKT2 is frequently upregulated in HER-2/neu-positive breast cancers and may contribute to tumor aggressiveness by enhancing cell survival

“…We suggest that activation of AKT2 in particular plays an important role in breast tumorigenesis based on the immunohistochemical analyses showing overexpression of AKT2 in the breast tumors. The cytoplasmic staining of phospho-AKT in tumors also is similar to previous reports (Sun et al, 2001a,b), and overlaps with the staining for AKT2 expression using both polyclonal AKT2 antibodies and a monoclonal AKT2 antibody previously used for the analysis of pancreatic tumors (Ruggeri et al, 1998). Because the phospho-speci®c, pan-AKT antibodies recognize equivalent phosphorylation sites in AKT1, AKT2 and AKT3, we acknowledge that our positively-stained para n-embedded tumor specimens may have activation of multiple AKT isoforms.…”

“…We have reported ampli®cation and overexpression of AKT2 in pancreatic and ovarian cancers (Bellacosa et al, 1995;Cheng et al, 1996;Ruggeri et al, 1998). In breast tumors, AKT3 over-expression has been reported in estrogen receptornegative breast tumors (Nakatani et al, 1999), and AKT1 activation has been reported in *40% of breast carcinomas (Sun et al, 2001a).…”

Mechanisms of apoptosis by c-Myc

“…Mutation of p53 or elevation of antiapoptotic members of the Bcl-2 family are paradigms in cancer. As outlined above, activation of AKT by various means in cancer cells is also likely to be important (Franke et al, 1997;Frisch and Ruoslahti, 1997;Ruggeri et al, 1998;Wu et al, 1998). However, the executioner machinery remains intact in cells transformed by c-Myc, which may o er an Achilles' heel to exploit.…”

Oncogenic transformation induced by membrane-targeted Akt2 and Akt3

“…For both Akt2 and Akt3 there are data suggesting a role in human cancer. Akt2 is ampli®ed and overexpressed in ovarian cancer, breast cancer and pancreatic cancer and Akt3 is overexpressed in breast and prostate cancer (Bellacosa et al, 1995;Cheng et al, 1992Cheng et al, , 1996Miwa et al, 1996;Nakatani et al, 1999b;Ruggeri et al, 1998). In this communication, we describe oncogenic transformation by Akt2 and Akt3 in experimental systems.…”