scholarly journals Assessing the order of critical alterations in prostate cancer development and progression by IHC: further evidence that PTEN loss occurs subsequent to ERG gene fusion

2013 ◽  
Vol 16 (2) ◽  
pp. 209-215 ◽  
Author(s):  
B Gumuskaya ◽  
B Gurel ◽  
H Fedor ◽  
H-L Tan ◽  
C A Weier ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Gene Fusion ◽  
Cancer Development ◽  
Pten Loss ◽  
Prostate Cancer Development

scholarly journals Both p110α and p110β isoforms of PI3K can modulate the impact of loss-of-function of the PTEN tumour suppressor

2012 ◽  
Vol 442 (1) ◽  
pp. 151-159 ◽  
Author(s):  
Inma M. Berenjeno ◽  
Julie Guillermet-Guibert ◽  
Wayne Pearce ◽  
Alexander Gray ◽  
Stewart Fleming ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Lines ◽  
Tumour Suppressor ◽  
Negative Regulator ◽  
Cancer Development ◽  
Pten Loss ◽  
Mouse Tissues ◽  
Primary Mouse ◽  
Prostate Cancer Development ◽  
The Impact

The PI3K (phosphoinositide 3-kinase) pathway is commonly activated in cancer as a consequence of inactivation of the tumour suppressor PTEN (phosphatase and tensin homologue deleted on chromosome 10), a major negative regulator of PI3K signalling. In line with this important role of PTEN, mice that are heterozygous for a PTEN-null allele (PTEN+/− mice) spontaneously develop a variety of tumours in multiple organs. PTEN is a phosphatase with selectivity for PtdIns(3,4,5)P3, which is produced by the class I isoforms of PI3K (p110α, p110β, p110γ and p110δ). Previous studies indicated that PTEN-deficient cancer cell lines mainly depend on p110β, and that p110β, but not p110α, controls mouse prostate cancer development driven by PTEN loss. In the present study, we investigated whether the ubiquitously expressed p110α can also functionally interact with PTEN in cancer. Using genetic mouse models that mimic systemic administration of p110α- or p110β-selective inhibitors, we confirm that inactivation of p110β, but not p110α, inhibits prostate cancer development in PTEN+/− mice, but also find that p110α inactivation protects from glomerulonephritis, pheochromocytoma and thyroid cancer induced by PTEN loss. This indicates that p110α can modulate the impact of PTEN loss in disease and tumourigenesis. In primary and immortalized mouse fibroblast cell lines, both p110α and p110β controlled steady-state PtdIns(3,4,5)P3 levels and Akt signalling induced by heterozygous PTEN loss. In contrast, no correlation was found in primary mouse tissues between PtdIns(3,4,5)P3 levels, PI3K/PTEN genotype and cancer development. Taken together, our results from the present study show that inactivation of either p110α or p110β can counteract the impact of PTEN inactivation. The potential implications of these findings for PI3K-targeted therapy of cancer are discussed.

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