Pten and other ptdins(3,4,5)p3 lipid phosphatases in breast cancer

Research output: Contribution to journalReview ArticleResearchpeer-review

32 Citations (Scopus)

Abstract

The phosphoinositide 3-kinase (PI3K)/AKT signalling pathway is hyperactivated in ~70% of breast cancers. Class I PI3K generates PtdIns(3,4,5)P3 at the plasma membrane in response to growth factor stimulation, leading to AKT activation to drive cell proliferation, survival and migration. PTEN negatively regulates PI3K/AKT signalling by dephosphorylating PtdIns(3,4,5)P3 to form PtdIns(4,5)P2 . PtdIns(3,4,5)P3 can also be hydrolysed by the inositol polyphosphate 5-phosphatases (5-phosphatases) to produce PtdIns(3,4)P2 . Interestingly, while PTEN is a bona fide tumour suppressor and is frequently mutated/lost in breast cancer, 5-phosphatases such as PIPP, SHIP2 and SYNJ2, have demonstrated more diverse roles in regulating mammary tumourigenesis. Reduced PIPP expression is associated with triple negative breast cancers and reduced relapse-free and overall survival. Although PIPP depletion enhances AKT phosphorylation and supports tumour growth, this also inhibits cell migration and metastasis in vivo, in a breast cancer oncogene-driven murine model. Paradoxically, SHIP2 and SYNJ2 are increased in primary breast tumours, which correlates with invasive disease and reduced survival. SHIP2 or SYNJ2 overexpression promotes breast tumourigenesis via AKT-dependent and independent mechanisms. This review will discuss how PTEN, PIPP, SHIP2 and SYNJ2 distinctly regulate multiple functional targets, and the mechanisms by which dysregulation of these distinct phosphoinositide phosphatases differentially affect breast cancer progression.

Original languageEnglish
Article number9189
Number of pages23
JournalInternational Journal of Molecular Sciences
Volume21
Issue number23
DOIs
Publication statusPublished - Dec 2020

Keywords

  • AKT
  • Breast cancer
  • Inositol polyphosphate phosphatases
  • Phosphatase tensin homolog deleted on chromosome 10 (PTEN)
  • Phosphoinositide 3-kinase (PI3K)
  • Proline rich inositol polyphosphate 5-phosphatase (PIPP)
  • Src homology 2-containing inositol phosphatase 2 (SHIP2)
  • Synaptojanin 2 (SYNJ2)

Cite this