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Phosphatase and tensin homologue deleted on chromosome 10 (PTEN), also referred to as mutated in multiple advanced cancers (MMAC1) and TGF-β regulated and epithelial cell enriched phosphatase (TEP1), was first discovered in 1997.1–3 Since its discovery, an entire network of interconnections to various other cellular pathways has been uncovered but its role continues to evolve. PTEN is frequently inactivated in somatic cancers and is ranked the second most mutated tumour suppressor gene after p53.4 5
This article highlights the important aspects of structure, function, mutations and role in cancer that are of relevance to the practicing pathologist. For more detailed information on these aspects the reader should refer to recently published articles.
The PTEN gene, mapped to 10q23.3, contains nine exons and encodes a 47 kD protein with 403 amino acids. Exons 1–6 code for the N-terminal domain, which consists of the first 185 amino acids, and contains the important phosphatase domain of the protein. This domain has an enlarged active site which contains the catalytic core. The C-terminal domain is made up of the remaining amino acids (186–403) and consists of the following subdomains: C2, which binds to phospholipids; two PEST sequences, which are responsible for protein stability; PDZ binding motif, which interacts with the phosphatase domain and various phosphorylation sites.
PTEN plays a role in numerous cell processes including ageing, angiogenesis, apoptosis, cell cycle progression, cell proliferation, chemotaxis, muscle contractility and DNA damage response.
PTEN encodes a dual specificity phosphatase with the ability to dephosphorylate both lipid and protein substrates.6 It is the main negative regulator of the PI3K/Akt pathway (figure 1)7 and achieves this by dephosphorylating PIP3 thereby opposing PI3K activity and resulting in subsequent downregulation of Akt.
In order to explain the effects of PTEN, the actions of the PI3K/Akt pathway will be briefly discussed. The PI3K/Akt pathway is a major signal transduction pathway that promotes cell growth and survival and contributes to the evasion of apoptosis, loss of cell cycle control and genomic instability during tumourigenesis.8 9 It also influences differentiation, actin rearrangements and membrane trafficking.
Akt promotes proliferation and survival by inhibiting a number of tumour suppressor-like signal molecules, such as bad, FOXO3 and TSC2 and activating oncogenes, such as mdm2, PDK1 and IKK. Evasion of apoptosis by Akt is mediated by its ability to decrease proapoptotic proteins such as bad, fasL, bim and p53, and to increase antiapoptotic factors such as NFκB. The PI3K/Akt pathway via mdm2 targets p53 for degradation by the proteasome system.10 11 The antagonistic effect of PTEN on the PI3K/Akt pathway maintains p53 stability.8 9 11 12
PTEN regulates key checkpoint proteins, such as, p27, p130, cyclin D1 and myc, thereby controlling cell cycle progression and DNA damage checkpoints.8 9 12 Specifically, PTEN upregulates p27 and downregulates cyclin D1 resulting in G1 arrest.13 Due to the various influences of PTEN it is not surprising that PTEN mutations result in diverse effects, such as centromere instability, double strand break repair defects, cell cycle checkpoint failure, resistance to apoptosis and sustained cell growth.14 15 PTEN also regulates proliferation and differentiation by inhibiting the mitogen-activated kinase pathway.16–18
PTEN is degraded in the cytoplasm by the ubiquitin-proteasome pathway. Interestingly, it is the polyubiquitinated PTEN that is degraded in the cytoplasm while the mono-ubiquitinated PTEN translocates to the nucleus where the ubiquitin is excised.19–21
PTEN mutations and other genetic alterations may impair PTEN functions. PTEN inactivation may be due to inappropriate subcellular compartmentalisation (normal islet cells of the pancreas show predominantly nuclear PTEN expression whereas pancreatic endocrine neoplasms show cytoplasmic PTEN),22 altered proteasome degradation and somatic intragenic mutations and epigenetic inactivation in sporadic tumours.23 PTEN alterations include a variety of possible post-translational modifications which may alter the phosphatase activity, direct subcellular localisation, affect PTEN complexes and influence protein stability.23–27
Normal cells usually show strong nuclear PTEN expression which is lost during transformation to neoplasia.
Altered regulation of PTEN, PTEN protein degradation or relocalisation may disrupt the signal network and tip the balance towards tumourigenesis.
The enlarged active site in the N-terminal domain which contains the catalytic core is a mutational hotspot, with approximately 30% of germline and sporadic mutations involving this core region.28 Most naturally occurring PTEN mutations are both lipid- and protein-phosphatase inactive while 90% of PTEN missense mutations reduce or remove lipid phosphatase activity.29 In contrast, 40% of all PTEN mutations involve the C2 subdomain.30 Evidence suggests that PTEN is haploinsufficient.31
PTEN abnormalities in tumours
Various PTEN abnormalities have been described in cancers.
Monoallelic PTEN loss has been reported in glioma (∼75%), breast (∼40–50%), prostate (∼42%), lung (∼37%) and colon (∼20%) cancers.32–36
Germline mutations in PTEN have been found in patients with Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, Lhermitte-Duclos disease, Proteus syndrome and Proteus-like syndrome.43–46 Cowden syndrome carries a high risk for breast, thyroid and endometrial cancers.
PTEN somatic mutations: the frequency varies widely among sporadic primary cancers with the highest observed in endometrial carcinoma and glioblastoma multiforme.40 47 48 PTEN alterations play a significant role in the carcinogenesis of the majority of sporadic endometrial carcinomas.49 It is believed that PTEN alterations or mutations occur in the precancerous stage or earlier in advance of mismatch repair deficiency in endometrial cancer.42 47 48 The increasing frequency of PTEN mutations and deletions is directly related to increasing grade of neoplasm from glioma to glioblastoma.50
PTEN and tumour behaviour
In mice, heterozygous loss of PTEN has been shown to lead to cancers in various organs or systems, such as prostate, thyroid, colon, lymphatic system, breast and endometrium.51 PTEN alterations are associated with metastasis and poor prognosis.52 Loss of 10q in pancreatic endocrine neoplasms is associated with malignant status.
In cancer cells with inactivated PTEN, restoration of PTEN functions directly or indirectly could potentially be used to treat these cancers. Because the PTEN pathway may be inactivated by a number of different mechanisms, there are a variety of options for targeted chemotherapy. Targets downstream of PTEN, such as PI3K, AKT and mTOR have also been considered.
Direct methods of PTEN restoration include introduction of wild-type PTEN by using viral or non-viral vectors.53 54 Indirect methods of restoring PTEN function include blocking upstream molecules such as growth factor receptor tyrosine kinases. Specific antibodies against growth factor receptor tyrosine kinases are already in use: trastuzumab for HER2 and cetuximab for EGFR. The response to trastuzumab is significantly worse in PTEN negative breast tumours.55 In cell viability assays the presence of PTEN increases trastuzumab response.55 Trastuzumab blocks ErbB2/Her2 signalling in many ways, one of which is by activating PTEN. Further, since PTEN is degraded by the ubiquitin-proteasome pathway, proteasome inhibitors may potentially be used to increase PTEN levels. Although monotherapy with mTOR inhibitors and their analogues only appear to target PTEN's lipid phosphatase activity,30 it has been shown that PTEN mutation positive cancer cells are hypersensitive to rapamycin inhibition of mTOR.56
Competing interests None.
Provenance and peer review Commissioned; internally peer reviewed.