PTEN loss in the continuum of common cancers, rare syndromes and mouse models

Abstract

PTEN is among the most frequently inactivated tumour suppressor genes in sporadic cancer. PTEN has dual protein and lipid phosphatase activity, and its tumour suppressor activity is dependent on its lipid phosphatase activity, which negatively regulates the PI3K-AKT-mTOR pathway. Germline mutations in PTEN have been described in a variety of rare syndromes that are collectively known as the PTEN hamartoma tumour syndromes (PHTS). Cowden syndrome is the best-described syndrome within PHTS, with approximately 80% of patients having germline PTEN mutations. Patients with Cowden syndrome have an increased incidence of cancers of the breast, thyroid and endometrium, which correspond to sporadic tumour types that commonly exhibit somatic PTEN inactivation. Pten deletion in mice leads to Cowden syndrome-like phenotypes, and tissue-specific Pten deletion has provided clues to the role of PTEN mutation and loss in specific tumour types. Studying PTEN in the continuum of rare syndromes, common cancers and mouse models provides insight into the role of PTEN in tumorigenesis and will inform targeted drug development.

Figure 1 |. Schematic of the PTEN protein.

PTEN contains two key domains that are required for its tumour suppressor function; the phosphatase (catalytic) domain (amino acids 14–185) with an active site included within the residues 123 and 130 (REF. 166), and the C2 (lipid membrane-binding) domain (amino acids 190–350). The importance of other domains such as the PDZ-binding domain (in grey; amino acids 401–403), which binds proteins containing PDZ domains, and the carboxy-terminal region (amino acids 351–400), which contains PEST sequences and may contribute to protein stability and activity, is less defined in the tumour suppressor functions of PTEN.

Figure 2 |. Canonical PTEN–PI3K–AKT–mTOR pathway.

PTEN opposes PI3K function, leading to inactivation of AKT crucial downstream target. When PTEN activity is decreased or absent, products of PI3K activate AKT through the activation of its upstream kinase phosphoinositide-dependent kinase 1 (PDK1; encoded by PDPK1). Other upstream regulators of the pathway include receptor tyrosine kinases (RTKs) such as ERBB2 and epidermal growth factor receptor (EGFR) that are important in breast and lung cancer, respectively (reviewed in REF. 171). Important downstream targets of AKT (such as p27, p21, FOXO and PAWR (also known as PAR4)) are involved in multiple functions that are crucial for tumour cell growth and survival (reviewed in REF. 8). mTOR activity is also increased when PTEN activity is lost, and mTOR itself has important targets, including AKT, as well as proteins required for protein translation such as ribosomal protein S6 kinase (S6K; encoded by RPS6KB1 and TPS6KB2) and eukaryotic initiation factor 4E binding protein (4EBP1; encoded by EIF4EBP1). mTOR exists in two different protein complexes, TORC1 and TORC2 (REF. 173). Inhibitors of TORC1 by drugs such as rapamycin can activate AKT by deactivating a negative-feedback loop mediated by S6K and insulin receptor substrate 1 (IRS1)^,. Proteins that can be targeted by drugs (as outlined in TABLE 2) are indicated in red. BAD, BCL-2-associated agonist of cell death; GSK3, glycogen synthase kinase 3; MAP3K5, apoptosis signal regulator kinase 1.