Csolle Mariah P, Ooms Lisa M, Papa Antonella, Mitchell Christina A
Cancer Program, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.
Int J Mol Sci. 2020 Dec 2;21(23):9189. doi: 10.3390/ijms21239189.
The phosphoinositide 3-kinase (PI3K)/AKT signalling pathway is hyperactivated in ~70% of breast cancers. Class I PI3K generates PtdIns(3,4,5)P 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)P to form PtdIns(4,5)P. PtdIns(3,4,5)P can also be hydrolysed by the inositol polyphosphate 5-phosphatases (5-phosphatases) to produce PtdIns(3,4)P. 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 expression is associated with triple negative breast cancers and reduced relapse-free and overall survival. Although 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.
磷酸肌醇3激酶（PI3K）/AKT信号通路在约70%的乳腺癌中被过度激活。I类PI3K在生长因子刺激下于质膜产生磷脂酰肌醇-3,4,5-三磷酸（PtdIns(3,4,5)P），导致AKT激活，从而驱动细胞增殖、存活和迁移。PTEN通过使PtdIns(3,4,5)P去磷酸化形成磷脂酰肌醇-4,5-二磷酸（PtdIns(4,5)P）来负向调节PI3K/AKT信号通路。PtdIns(3,4,5)P也可被肌醇多磷酸5-磷酸酶（5-磷酸酶）水解产生磷脂酰肌醇-3,4-二磷酸（PtdIns(3,4)P）。有趣的是，虽然PTEN是一种真正的肿瘤抑制因子，且在乳腺癌中经常发生突变/缺失，但诸如PIPP、SHIP2和SYNJ2等5-磷酸酶在调节乳腺肿瘤发生中发挥了更多样化的作用。其表达降低与三阴性乳腺癌以及无复发生存期和总生存期缩短有关。尽管其缺失会增强AKT磷酸化并促进肿瘤生长，但在一种乳腺癌癌基因驱动的小鼠模型中，这也会在体内抑制细胞迁移和转移。矛盾的是，SHIP2和SYNJ2在原发性乳腺肿瘤中表达增加，这与侵袭性疾病和生存期缩短相关。SHIP2或SYNJ2的过表达通过依赖AKT和不依赖AKT的机制促进乳腺肿瘤发生。本综述将讨论PTEN、PIPP、SHIP2和SYNJ2如何分别调节多个功能靶点，以及这些不同的磷酸肌醇磷酸酶失调差异影响乳腺癌进展的机制。
