PI3K Isoforms Have Spatially Distinct Roles in PTEN Hamartoma Tumor Syndrome

PTEN hamartoma tumor syndrome (PHTS) is a collective term for a group of disorders caused by germline PTEN mutations that are characterized by the formation of multiple benign skin hamartomas and often associated with increased cancer susceptibility. PTEN is a lipid phosphatase and tumor suppressor that counteracts the lipid kinase activity of class Ia phosphoinositide 3-kinases (PI3K). Wang and colleagues evaluated the roles of the epithelially expressed PI3K catalytic isoforms p110α and p110β in the development and maintenance of PHTS using a mouse model that specifically lacks Pten expression in the epidermis. Deletion of either PI3K isoform significantly delayed but did not prevent hamartoma formation in Pten-deficient mice. However, deletion of both p110α and p110β prevented AKT hyperphosphorylation, restored normal skin thickness and architecture, and completely prevented the formation of hamartomas in Pten-deficient mice, indicating that the two isoforms play essential, nonredundant roles in PHTS. Consistent with this possibility, p110α and p110β were found to be differentially expressed in the epidermal compartments of Pten-null skin, with higher p110α expression in suprabasal cells and higher p110β expression in the basal cell layer. Moreover, p110α was specifically required for the survival of suprabasal cells in the absence of Pten, whereas p110β promoted basal cell hyperproliferation. Strikingly, treatment of the Pten-deficient mice with a submaximal, well-tolerated dose of the pan-PI3K inhibitor BKM120 that inhibits both p110α and p110β completely blocked hamartoma formation as long as the mice were on treatment. A clinically relevant dose of BKM120 also induced rapid, dramatic regression of advanced hamartomas. In addition to revealing spatially distinct roles of PI3K isoforms in the skin, these findings provide a rationale for use of PI3K inhibitors to prevent and treat hamartomas in patients with PHTS.

Wang Q, Von T, Bronson R, Ruan M, Mu W, Huang A, et al. Spatially distinct roles of class Ia PI3K isoforms in the development and maintenance of PTEN hamartoma tumor syndrome. Genes Dev 2013;27:1568–80.