PTEN is a tumor suppressor gene that is frequently deleted or mutated in prostate, endometrial and breast cancer. This lipid phosphatase regulates cell survival, growth and migration.

PTEN suppresses phosphoinositol-3-kinase (PI3K) signaling, thereby down-regulating downstream mediators, including the oncogenic serine-threonine kinase AKT, which in turn regulates the mTOR (mammalian target of rapamycin) growth pathway.

PTEN activity causes cell-cycle arrest and apoptosis as well as inhibition of cell motility. It has been proposed that PTEN blocks the cell cycle by increasing the transcription of the p27 Cip/Kip cell-cycle inhibitor and stabilizing the protein.

Function

As the primary phosphatase of phosphatidylinositol (3,4,5)-trisphosphate, PTEN has a central role in reigning in the phosphoinositide 3-kinase (PI 3-kinase) network to control cellular homeostasis.

Cells that lack PTEN are unable to regulate the PtdIns 3-kinase programme, which stimulates a variety of cellular phenotypes that favour oncogenesis.

 tumour suppressor
 regulation of basic cellular functions

• cell migration
• cell size
• contractility of cardiac myocytes
• chemotaxis.

Pathology

Phosphatase and tensin homologue, deleted on chromosome 10 (PTEN) gene, mapped on chromosome 10q23, is frequently deleted in many human cancers but at particularly high frequency in endometrial carcinomas and glioblastomas. With loss of PTEN, therefore, cells are released into the cell cycle.

Mutations of the PTEN gene cause a dysregulation of the phosphoinositol-3-kinase/Akt pathway.

 germline mutations

• Lhermitte-Duclos disease (dysplastic gangliocytoma of the cerebellum)(MIM.158350)
• autosomal recessive VATER association with hydrocephalus (MIM.276950)
• Proteus syndrome (MIM.176920)
• PTEN-associated tumor syndromes
  • Cowden disease (MIM.158350) (80%)
  • Bannayan-Zonana syndrome or Bannayan-Ruvalcaba-Riley syndrome (BRRS) (MIM.153480) (60%)

 somatic mutations in cancer

• endometrial adenocarcinoma
• prostatic adenocarcinoma
• mammary adenocarcinoma
• malignant melanoma
• oligodendroglioma
• glioblastoma (24%)
• epidermoid carcinoma of head and neck

References

 Brader S, Eccles SA. Phosphoinositide 3-kinase signalling pathways in tumor progression, invasion and angiogenesis. Tumori. 2004 Jan-Feb;90(1):2-8. PMID: #15143962#

 Goberdhan DC, Wilson C. PTEN: tumour suppressor, multifunctional growth regulator and more. Hum Mol Genet. 2003 Oct 15;12 Spec No 2:R239-48. PMID: #12928488#

 Eng C. PTEN: one gene, many syndromes. Hum Mutat. 2003 Sep;22(3):183-98. PMID: #12938083#

 Sulis ML, Parsons R. PTEN: from pathology to biology. Trends Cell Biol. 2003 Sep;13(9):478-83. PMID: #12946627#

 Wishart MJ, Dixon JE. PTEN and myotubularin phosphatases: from 3-phosphoinositide dephosphorylation to disease. Trends Cell Biol. 2002 Dec;12(12):579-85. PMID: #12495846#

 Waite KA, Eng C. Protean PTEN: form and function. Am J Hum Genet. 2002 Apr;70(4):829-44. PMID: #11875759#

 Ali IU. Gatekeeper for endometrium: the PTEN tumor suppressor gene. J Natl Cancer Inst. 2000 Jun 7;92(11):861-3. PMID: #10841815#