Review
Non-genomic loss of PTEN function in cancer: not in my genes

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Loss of function of the phosphatase and tensin homolog (PTEN) tumour suppressor contributes to the development of many cancers. However, in contrast to classical models of tumour suppression, partial loss of PTEN function appears to be frequently observed in the clinic. In addition, studies of both humans and mice with reductions in PTEN gene dosage indicate that even partial loss of PTEN function is sufficient to promote some cancer types, particularly in the breast. PTEN expression appears to be tightly controlled both transcriptionally and post-transcriptionally, with several recent studies implicating oncogenic microRNAs in PTEN suppression. The lipid phosphatase activity of PTEN can also be regulated post-translationally via inhibitory phosphorylation, ubiquitination or oxidation. Here we discuss these multiple mechanisms of PTEN regulation. We also put into context recent proposals that changes in this regulation can drive tumour development and address the accompanying evidence for their clinical significance.

Introduction

Cancer is believed to develop because some cells within an organism become aberrant and hyperproliferative through the accumulation of genetic and epigenetic changes. The genes most frequently modified in cancer are frequently categorised into two groups: oncogenes, in which a gain of function drives tumour formation and tumour suppressors, in which a loss of function promotes tumour development. The lipid phosphatase, PTEN, is a tumour suppressor originally identified by two research groups in 1997 1, 2. Mutations of the PTEN gene occur at some significant frequency in almost all human tumour types and mutation of at least one allele occurs in one third or more of breast, colon, prostate and lung tumours {[3] and the Cosmic (collection of Somatic Mutations in Cancer) database; http://www.sanger.ac.uk/genetics/CGP/cosmic/}. Accordingly, in a recent cancer genomics study aiming to distinguish between deletions driven by chromosomal instability and those driven by phenotypic selection, PTEN was proposed to be the tumour suppressor locus in the human genome with the greatest selection for loss [4].

Biochemically, PTEN is a phosphatase that dephosphorylates phosphatidylinositol 3,4,5-trisphosphate (PIP3), the lipid product of the class I phosphoinositide 3-kinases (PI3K) [5]. This discovery was rapidly followed by a wealth of genetic and cell-based evidence showing that PTEN is a ubiquitous inhibitor of PI3K-dependent signalling [6]. PI3K/PTEN signalling (and the PIP3 lipid they control) influence cell behaviour through a large and diverse set of PIP3-binding proteins, the best characterised of which are the AKT protein kinases 7, 8, 9. In this way, PI3K and PTEN orchestrate cell responses to growth factors, cytokines, integrins and other intercellular mediators and contribute to the growth, motility, survival and metabolic responses of many cell types. PTEN also has robust protein phosphatase activity in vitro and has been proposed to play a tumour suppressor role in the nucleus, independently of plasma membrane-localised PIP3 10, 11, 12, 13. However, the significance of these other mechanisms of action is currently unclear and space constraints do not allow us to consider them further here. The loss of PTEN function in tumours should also be viewed in the context of the broader PI3K pathway, in which an alternative route of PIP3 metabolism is provided by the family of phosphoinositide 5-phosphatases, in particular the SHIP enzymes, which convert PIP3 to the alternate signal PI(3,4)P2 (Figure 1).

Section snippets

Partial loss of PTEN function

For many years the ‘gold standard’ of evidence for functional dysregulation in human tumours has been genetic mutation data, in large part due to apparent clarity provided by the identification of novel sequence variants and the usually robust nature of DNA sequence data. Accordingly, it has been clear for many years that the great majority of PTEN mutations identified in tumours inhibit the function of the enzyme 14, 15. However, improvements in other technologies in tumour pathology,

PTEN function: constitutive activity and post-translational inhibition?

The PTEN gene encodes a single 403 amino acid protein (Figure 2). Genetic deletion or RNAi-mediated knockdown of PTEN in many (but not all) unstimulated cultured cells or tissues leads to robust increases in PIP3-dependent AKT phosphorylation and (where measured) intracellular PIP3 levels 35, 36, 37. This strongly argues that PTEN plays a continuous physiological role in suppressing PIP3 levels in many cell types and is consistent with the constitutive activity of PTEN purified from multiple

Epigenetic and transcriptional regulation of PTEN

In addition to gene mutations or deletions, and protein post-translational modifications and protein–protein interactions affecting its activity and stability, PTEN undergoes a complex regulation by multiple epigenetic and transcriptional mechanisms (Figure 3). This additional level of regulation appears to play a crucial role in diverse cancer or metabolic disorders in which PTEN expression is altered with no apparent muations or deletions of the gene.

Cancer therapeutics targeting PTEN function?

The PI3K signalling pathway appears to contribute to driving the formation of most human tumours and frequently to resistance of these tumours to existing therapies 19, 127. The pathway is therefore the target of intense drug discovery activity 128, 129. The emergence of evidence, discussed in this review, that tumour development is promoted by modifiers of PTEN function has raised the possibility of these modifiers as novel drug targets. The most appealing targets would appear to be functional

Concluding remarks

In summary, novel insight into the mechanisms leading to loss of PTEN function in tumours is not only likely to identify novel therapeutic approaches but also provides a deeper understanding of oncogenic PI3K/PTEN signalling that will assist the development and eventual use of the many agents targeting this pathway that are under development. It seems likely that continued intense activity in this broad research field will provide many areas of progress and eventually clinical success stories.

Acknowledgements

Work in the Leslie laboratory is supported by the UK Medical Research Council (grant G0801865), the Association for International Cancer research (grant 08-0497) and the pharmaceutical companies of the Dundee Signal Transduction Therapy Consortium (Astra Zeneca, Boehringer Ingelheim, GlaxoSmithKline, Merck Serono, and Pfizer) and in the Foti laboratory by the Swiss National Science Foundation (grant No. 310000-120280/1) and the Swiss Research against Cancer Foundation (grant No.

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