Targeting aberrant signaling in the EGFR1/HER2/PI3K/PTEN/Akt/mTORC1/GSK-3 pathway : Novel therapeutic interventions in breast cancer

Abstract

Breast cancer is attributed to being the second most deadly cancer in American women. Approximately 1 in 8 women will be diagnosed with breast cancer during her lifetime, and prognosis is dependent upon the genetic make-up of both the patient and the cancer. The EGFR1/HER/PI3K/PTEN/Akt/mTORC1/GSK-3 pathway plays prominent roles in an array of cellular functions including malignant transformation of cells (tumorigenesis), prevention of apoptosis, drug resistance, and metastasis. This pathway is frequently altered in breast cancer due to mutations or aberrant expression of genes (HER2, EGFR1, PIK3CA, PTEN, and RB), as well as other oncogenes. Expression of this pathway and its components can lead to resistance and sensitivities to currently available therapeutics. The therapeutic resistance/sensitivities are considered significant problems in the practices of clinicians who treat the disease. A clearer understanding of how deregulation of the EGFR1/HER2/PI3K/PTEN/Akt/mTORC1/GSK-3 pathway plays a role in breast cancer is necessary in order to take preventative measures in dealing with potential drug treatment complications. This study focused on examining the effects of cell signaling, particularly on a key cellular component, the kinase GSK-3[beta]. Properties associated with cellular transformation, drug resistance and sensitivity in relation with GSK-3[beta] were characterized.