The oncogenic properties of mutant p110α and p110β phosphatidylinositol 3-kinases in human mammary epithelial cells

The PIK3CA gene encoding the p110 alpha subunit of Class 1A phosphaticlylinositol 3-kinases (PI3Ks) is frequently mutated in human tumors. Mutations in the PIK3CB gene encoding p110 beta, the only other widely expressed Class 1A PI3K, have not been reported. We compared the biochemical activity and transforming potential of mutant forms of p110 alpha and p110 beta in a human mammary epithelial cell system. The two most common tumor-derived alleles of p110 alpha, H1047R and E545K, potently activated PI3K signaling. Human mammary epithelial cells expressing these alleles grew efficiently in soft agar and as orthotopic tumors in nude mice. We also examined a third class of mutations in p110a, those in the p85-binding domain. A representative tumor-derived p85-binding-domain mutant R38H showed modestly reduced p85 binding and weakly activated PI3K/Akt signaling. In contrast, a deletion mutant lacking the entire p85-binding domain efficiently activated PI3K signaling. When we constructed in p110 beta a mutation homologous to the E545K allele of p110a,the resulting p110 beta mutant was only weakly activated and allowed minimal soft-agar growth. However, a gene fusion of p110 beta with the membrane anchor from c-Src was highly active and transforming in both soft-agar and orthotopic nude mouse assays. Thus, although introduction of activating mutations from p110 alpha at the corresponding sites in p110 beta failed to render the enzyme oncogenic in human cells, the possibility remains that other mutations might activate the beta isoform.