Breast cancer is the most common cancer in women and is increasing in both the developed and developing countries. There is an urgent need to understand the precise mechanisms of tumour development in breast cancer, to develop new treatment strategies and to identify predictive markers for tumour aggressiveness and therapy resistance.
A protein called protein kinase B (PKB, also called Akt) is frequently elevated in breast cancers and has been implicated as a key player in breast cancer development and progression. The activation level of PKB is also thought to correlate with patient outcome. However, the function of the three isoforms of PKB in mediating the crucial responses is unknown. We have developed a set of antisense phosphorothioate oligonucleotide probes that target antisense-active regions in PKB and that enable >90% knockdown of all three known PKB isoforms (alpha, beta and gamma), either individually or in various combinations, including removal of all three isoforms together. We have demonstrated that these agents specifically and potently prevent the growth of breast cancer cells. Application of these antisense agents offers a unique opportunity to understand how PKB works and contributes to breast cancer, and to provide insight into the role of signalling by individual PKB isoforms in breast cancer cells. Such work may also identify clinically relevant markers of disease, thereby enabling better predictors of patient outcome, and provide the necessary intellectual framework for the development of PKB-isoform selective inhibitors (for example, antisense oligonucleotides, small chemical inhibitors) as novel therapeutic agents.