The Role of Phosphoinositide 3-Kinase in Breast Cancer: An Overview

摘要

The family of lipid kinases termed phosphoinositide 3-kinases (PI3Ks), discovered in the 1980s, have been determined to have key roles in several cellular processes critical for tumorigenesis and tumor maintenance, including metabolism, growth, survival, and motil-ity. Inappropriate co-option of PI3K signaling is one of the most frequent occurrences found in human malignancies. As a result of its pivotal role in cancer, this pathway has been a major focus of cancer drug development. Despite many therapeutic agents already developed and under clinical investigation, it still remains unclear how best to define tumors most likely to benefit from these select drug therapies, what PI3K family members will be the most relevant to target for maximal therapeutic benefit, and whether certain members will be more appropriate for specific tumors. Simply stated, the PI3K family of related intracellular signal transducer enzymes phosphorylate the 3'-OH group on phospha-tidylinositols in the plasma membrane that subsequently leads to recruitment of the protein Ser/Thr-kinase, Akt, to the cell membrane. It is there that Atk becomes activated. The central component is the heterodimer phosphatidylinositol 3-kinase. This heterodimer is composed of 2 subunits: the regulatory p85 subunit and the catalytic p110 subunit. This PI3K-Akt signaling cascade is activated via several different mechanisms. It can either be activated directly by the GTPase protein Ras, or following membrane growth factor receptor tyrosine kinase activation. When activated, the inhibitory effect of the p85 is released, allowing for activation of the p110 catalytic subunit, which in turn converts membrane-related phosphatidylinositol-3,5 bisphosphonate (PIP2) to its tri-phosphate (PIP3) form. PIP3 is responsible for Akt phos-phorylation and it is this phosphorylation that results in many of the cell mediators of the PI3K pathway. Activation of this pathway has many downstream effects, including eventual alterati...