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PTEN and Other PtdIns(3,4,5)P3 Lipid Phosphatases in Breast Cancer

Cancer Program, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia
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Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(23), 9189; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239189
Received: 4 November 2020 / Revised: 25 November 2020 / Accepted: 1 December 2020 / Published: 2 December 2020
(This article belongs to the Special Issue Phosphoinositides and Downstream Signalling Molecules)
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. View Full-Text
Keywords: phosphoinositide 3-kinase (PI3K); AKT; inositol polyphosphate phosphatases; phosphatase tensin homolog deleted on chromosome 10 (PTEN); proline rich inositol polyphosphate 5-phosphatase (PIPP); Src homology 2-containing inositol phosphatase 2 (SHIP2); synaptojanin 2 (SYNJ2); breast cancer phosphoinositide 3-kinase (PI3K); AKT; inositol polyphosphate phosphatases; phosphatase tensin homolog deleted on chromosome 10 (PTEN); proline rich inositol polyphosphate 5-phosphatase (PIPP); Src homology 2-containing inositol phosphatase 2 (SHIP2); synaptojanin 2 (SYNJ2); breast cancer
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MDPI and ACS Style

Csolle, M.P.; Ooms, L.M.; Papa, A.; Mitchell, C.A. PTEN and Other PtdIns(3,4,5)P3 Lipid Phosphatases in Breast Cancer. Int. J. Mol. Sci. 2020, 21, 9189. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239189

AMA Style

Csolle MP, Ooms LM, Papa A, Mitchell CA. PTEN and Other PtdIns(3,4,5)P3 Lipid Phosphatases in Breast Cancer. International Journal of Molecular Sciences. 2020; 21(23):9189. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239189

Chicago/Turabian Style

Csolle, Mariah P.; Ooms, Lisa M.; Papa, Antonella; Mitchell, Christina A. 2020. "PTEN and Other PtdIns(3,4,5)P3 Lipid Phosphatases in Breast Cancer" Int. J. Mol. Sci. 21, no. 23: 9189. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239189

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