Phosphoinositide 3-kinase signalling in breast cancer: how big a role might it play?

Abstract

Phosphoinositide 3-kinase (PI3K) was first identified as a lipid kinase activity associated with the products of viral oncogenes and with activated protein-tyrosine kinases. Since those early studies, the PI3K superfamily has grown to embrace at least 12 structurally and functionally related enzymes present in the human genome, some of which have protein kinase activity but not lipid kinase activity. Evidence is emerging that PI3K superfamily members, and components of PI3K signalling, play a role in the development of many human cancers. In this review, the PI3K family of enzymes and their signalling is reviewed, with particular reference to possible involvement in breast cancer.

Figure 1

The phosphoinositide 3-kinase (PI3K) superfamily. Schematic representation of the catalytic subunits of the PI3K superfamily of enzymes. The names of the kinases are given on the left, together with their size (kDa). Classification by class is indicated by the bars on the right. Recognised domains are indicated. ATM/ATR/DNA-PK, Ataxia telangiectasia mutated/ataxia telangiectasia related/DNA-dependent protein kinase; FAT, domain present in FKBP rapamycin-associated protein/target of rapamycin (TOR), ATM and TRRAP (ATM-related) proteins; FATC, C-terminal domain found only in FAT domain containing proteins; FRB, FKBP12/rapamycin binding domain; HEAT, domain found in Huntington, EF3, a subunit of protein phosphatase 2A and TOR; HR1-HR4, homology region; p85 BD, p85 binding domain; PH, pleckstrin homology; PX, phox homology; RBD, Ras binding domain.

Figure 2

Phosphoinositide 3-kinase (PI3K) signalling and cancer. Schematic signalling pathway indicating the interactions that occur between known breast cancer oncogenes (ErbB2, Src) and tumour suppressors (PTEN, BRCA1) with components of the PI3K signalling cassette. Direct physical interactions are shown with solid arrows. Processes involving several steps are indicated with a dashed arrow; +, an activation step. Blunt arrows indicate inhibitory effects. Akt, Protein kinase B; ATM, ataxia telangiectasia mutated; ER, oestrogen receptor; 3-Ptase and 5-Ptase, phosphoinositide 3-phosphatase and phosphoinositide 5-phosphatase activities; PTEN, phosphatase and tensin homolog deleted on chromosome 10; TOR, target of rapamycin.