Are we missing the mTOR target in breast cancer?

Abnormalities in the PI3K/Akt/mTOR intracellular signalling pathway have been implicated in several forms of human cancer. The central component of the pathway is the phosphatidylinositol 3-kinase (PI3K) heterodimer which comprises the p85 regulatory and p110 catalytic subunit, and mutations in the catalytic domain of PI3K have been identified in 20–25% of breast cancers [1, 2]. A further 15–35% of breast cancer patients demonstrate reduced expression of PTEN (phosphatase and tensin homologue deleted on chromosome ten), an endogenous inhibitor of the PI3K/AKT pathway [3]. Akt is the ultimate effector of the pathway and directs a multitude of intracellular effects related to growth, glucose metabolism, protein synthesis and cell survival. Activation of the PI3K/Akt pathway provides a cell with unrestricted growth and survival signals, and one important downstream consequence is the alleviation of the suppression by the tuberous sclerosis protein complex (TSC1/2) of the mammalian target of rapamycin (mTOR) [4]. There are at least two groups of mTOR proteins, and the key protein involved in transmitting signals from PI3K/Akt is the mTORC1 complex. Within cells, mTORC1 plays a critical role in the transduction of proliferative signals through phosphorylation of the translational regulator 4E-BP1 (eukaryotic initiation factor 4E-binding protein) and the ribosomal protein p70s6k (the 70-kDa S6 kinase) that facilitate translation of mRNAs into proteins [5, 6]. In recent years our understanding of this pathway in breast cancer has been exploited by the development of a number of targeted anti-cancer therapeutics, with mTOR inhibitors being the most clinically developed to date.