ABSTRACT
When activated, the serine/threonine kinase AKT mediates an antiapoptotic signal implicated in chemoresistance of various cancers. The mechanism(s) of AKT activation are unknown, though overexpression of HER-2/neu has been implicated in breast cancer. Therefore, we determined the incidence of activated AKT in human pancreatic cancer, whether HER-2/neu is involved in AKT activation, and if AKT activation is associated with biologic behaviour. HER-2/neu expression and AKT activation were examined in seven pancreatic cancer cell lines by Western blotting. The in vitro effect of HER-2/neu inhibition on AKT activation was similarly determined. Finally, 78 pancreatic cancer specimens were examined for AKT activation and HER-2/neu overexpression, and correlated with the clinical prognostic variable of histologic grade. HER-2/neu was overexpressed in two of seven cell lines; these two cell lines demonstrated the highest level of AKT activation. Inhibition of HER-2/neu reduced AKT activation in vitro. AKT was activated in 46 out of 78 (59%) of the pancreatic cancers; HER-2/neu overexpression correlated with AKT activation (P=0.015). Furthermore, AKT activation was correlated with higher histologic tumour grade (P=0.047). Thus, it is concluded that AKT is frequently activated in pancreatic cancer; this antiapoptotic signal may be mediated by HER-2/neu overexpression. AKT activation is associated with tumour grade, an important prognostic factor.
Subject(s)
Adenocarcinoma/enzymology , Pancreatic Neoplasms/enzymology , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins/metabolism , Antibodies, Monoclonal/pharmacology , Enzyme Activation , Humans , Pancreatic Neoplasms/pathology , Prognosis , Proto-Oncogene Proteins c-akt , Receptor, ErbB-2/immunology , Receptor, ErbB-2/metabolism , Receptor, ErbB-2/physiology , Tumor Cells, CulturedABSTRACT
Activation of the serine/threonine kinase AKT is common in pancreatic cancer; inhibition of which sensitises cells to the apoptotic effect of chemotherapy. Of the various downstream targets of AKT, we examined activation of the NF-kappaB transcription factor and subsequent transcriptional regulation of BCL-2 gene family in pancreatic cancer cells. Inhibition of either phosphatidylinositol-3 kinase or AKT led to a decreased protein level of the antiapoptotic gene BCL-2 and an increased protein level of the proapoptotic gene BAX. Furthermore, inhibition of AKT decreased the function of NF-kappaB, which is capable of transcriptional regulation of the BCL-2 gene. Inhibiting this pathway had little effect on the basal level of apoptosis in pancreatic cancer cells, but increased the apoptotic effect of chemotherapy. The antiapoptotic effect of AKT activation in pancreatic cancer cells may involve transcriptional induction of a profile of BCL-2 proteins that confer resistance to apoptosis; alteration of this balance allows sensitisation to the apoptotic effect of chemotherapy.
Subject(s)
Adenocarcinoma/genetics , Adenocarcinoma/physiopathology , Apoptosis , Gene Expression Regulation, Neoplastic , NF-kappa B/pharmacology , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/physiopathology , Proto-Oncogene Proteins c-bcl-2/pharmacology , Proto-Oncogene Proteins/biosynthesis , Humans , Protein Serine-Threonine Kinases , Protein-Tyrosine Kinases , Proto-Oncogene Proteins c-akt , Proto-Oncogene Proteins c-bcl-2/biosynthesis , Proto-Oncogene Proteins c-bcl-2/genetics , Transcription, Genetic , Tumor Cells, CulturedABSTRACT
Sentinel lymph node biopsy (SLNB) is an emerging surgical technique to improve lymph node staging for breast cancer. Despite the rapid development of this technique, there remain aspects of SLNB that need to be further defined to provide a standardized approach. Variables, including patient selection, technical details for the performance of SLNB, extent of pathologic evaluation of the sentinel lymph node, and the impact of micrometastases, are areas of controversy. This paper reviews the controversies and discusses available data as well as personal experience and opinion.
