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

Top Cited Papers
Publisher Website
Google Scholar
Abstract
PTEN hamartoma tumour syndrome (PHTS) is a group of syndromes characterized by benign growths and a high risk for cancers of the breast, endometrium and thyroid. Cowden syndrome is the best characterized of these and 85% of patients have germline PTEN mutations. The range of abnormalities in patients with PHTS varies from patient to patient. Somatic PTEN mutations and deletions, and inactivation of PTEN by methylation or microRNA silencing, are common in multiple tumour types. These include the classical PHTS-associated tumours like breast, endometrium and thyroid, but also tumours of the central nervous system, prostate, lung, pancreas, liver and adrenal glands, as well as melanoma, leukaemia and lymphoma. Mouse models of Cowden syndrome, in which a single allele of Pten is deleted or mutated, exhibit characteristic Cowden syndrome phenotypes. Tumour types are very much dependent on the genetic background of the mice suggesting that there may be genetic risk factors for PHTS penetrance in humans. Tissue-specific deletion of Pten in mice can lead to rapid, slow or no tumours, depending on the tissue type. In some cases, tissue-specific Pten deletion can cooperate with other genetic alterations to enhance tumorigenesis. These mouse models have validated mutation or loss of PTEN as an aetiological factor in similar human tumours. PTEN is a lipid phosphatase that acts as a negative regulator of the PI3K–AKT–mTOR pathway, which is an important regulator of cell growth and survival. As such, pharmacological inhibition of this pathway may be exploited for therapy of tumours with altered PTEN, or for tumour prevention in patients with PHTS.