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Int J Mol Sci ; 21(23)2020 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-33276499

RESUMO

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.


Assuntos
Neoplasias da Mama/metabolismo , Suscetibilidade a Doenças , Metabolismo dos Lipídeos , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases/metabolismo , Neoplasias da Mama/etiologia , Neoplasias da Mama/patologia , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Feminino , Humanos , Inositol Polifosfato 5-Fosfatases/metabolismo , Proteínas Oncogênicas/genética , Proteínas Oncogênicas/metabolismo , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases/genética , Monoéster Fosfórico Hidrolases/genética , Monoéster Fosfórico Hidrolases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo
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