PIKing the right isoform: the emergent role of the p110β subunit in breast cancer

Class IA phosphoinositide-3'-kinases (PI3Ks) regulate many cellular processes. Despite a clear implication of PI3K in cancer, the involvement of each of its isoforms namely p110 alpha and p110 beta in the development of breast cancer remains elusive. Until recently, the spotlight was given to the alpha subunit; however, the p110 beta isoform has now emerged as an interesting target as well. In order to determine the importance of both these subunits in breast cancer, we aimed to study the expression of p110 alpha and p110 beta in a series of invasive breast carcinomas. We constructed tissue microarrays from 315 invasive breast carcinomas and performed immunohistochemistry for p110 alpha and beta, correlating the expression patterns with clinicopathological parameters. Furthermore, overall survival was analysed through Kaplan-Meier survival curves and Cox regression. We found that p110 subunits are expressed in 23.8% of invasive breast carcinomas, of which 11.8% express p110 alpha and 15.2% p110 beta. The p110 alpha positive tumours correlated with hormone receptor (HR) expression, and were not associated with overall survival. The membrane expression of p110 beta was associated with worse prognosis. This was due to its link to HER2-overexpression, lower age of onset, higher grade, lymph node involvement, distant metastasis and was inversely associated with HR status. Furthermore, p110 beta expression was associated with worse overall survival. Importantly our results indicate a role for the beta subunit in the development/progression of HER2-overexpressing tumours, highlighting possible therapeutic associations between HER2 and p110 beta inhibitors.