Both p110 alpha and p110 beta isoforms of PI3K can modulate the impact of loss-of-function of the PTEN tumour suppressor

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)P-3, which is produced by the class I isoforms of PI3K (p110 alpha, p110 beta, p110 gamma and p110 delta). Previous studies indicated that PTEN-deficient cancer cell lines mainly depend on p110 beta, and that p110 beta, but not p110 alpha, controls mouse prostate cancer development driven by PTEN loss. In the present study, we investigated whether the ubiquitously expressed p110 alpha can also functionally interact with PTEN in cancer. Using genetic mouse models that mimic systemic administration of p110 alpha-or p110 beta-selective inhibitors, we confirm that inactivation of p110 beta but not p110 alpha, inhibits prostate cancer development in PTEN+/- mice, but also find that p110 alpha inactivation protects from glomerulonephritis, pheochromocytoma and thyroid cancer induced by PTEN loss. This indicates that p110 alpha can modulate the impact of PTEN loss in disease and tumourigenesis. In primary and immortalized mouse fibroblast cell lines, both p110 alpha and p110 beta controlled steady-state PtdIns(3,4,5)P-3 levels and Akt signalling induced by heterozygous PTEN loss. In contrast, no correlation was found in primary mouse tissues between PtdIns(3,4,5)P-3 levels, PI3K/PTEN genotype and cancer development. Taken together, our results from the present study show that inactivation of either p110 alpha or p110 beta can counteract the impact of PTEN inactivation. The potential implications of these findings for PI3K-targeted therapy of cancer are discussed.