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.
Highlights
Breast cancer is the most common cancer affecting women and the second leading cause of cancer death [1]
Breast cancers are classified into four major tumour subtypes based on expression of growth factor and hormone receptors, including estrogen receptor (ER), progesterone receptor (PR), and epidermal growth factor receptor 2 (ErbB2/HER2); this classification contributes to therapy decisions and provides prognostic significance [3]
These findings demonstrate that under suboptimal and stressful growing conditions, loss of phosphatase tensin homolog deleted on chromosome 10 (PTEN) protein function triggers a failsafe mechanism in a cell-autonomous manner, that can be exploited in combination therapies with AKT inhibitors for breast cancer treatment [64]
Summary
Breast cancer is the most common cancer affecting women and the second leading cause of cancer death [1]. In relapsed chronic lymphocytic leukemia (CLL), idelalisib, a selective small-molecule inhibitor of p110δ, an isoform of the Class 1 PI3K catalytic subunit that is highly expressed in lymphoid cells, in combination with the CD20 monoclonal antibody rituximab, significantly improved progression-free and overall survival [9]. Despite these promising results, PI3K inhibitors have only shown modest single-agent therapeutic efficacy, highlighting the need for a better understanding of how PI3K and phosphoinositide signalling is mechanistically regulated in cancer. Activated AKT phosphorylates numerous cytosolic and nuclear targets including GSK3β, PRAS40, FOXO, mTORC1 and p27 to regulate cell metabolism, proliferation, survival, and migration [14]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
