PI3K activity in mammary epithelium is dependent on p110α and is negatively modulated by p110β.

  • Major finding: PI3K activity in mammary epithelium is dependent on p110α and is negatively modulated by p110β.

  • Mechanism: p110β competes with p110α for receptor binding to fine-tune PI3K activity.

  • Impact: Selective inhibition of p110α may be an effective treatment for HER2-positive breast cancer.

Aberrant growth factor signaling is common in cancer. Class Ia phosphoinositide 3-kinase (PI3K) is a critical effector of growth factor signaling and therefore an attractive target for cancer therapy. PI3K is a lipid kinase comprised of a p85 regulatory subunit, which interacts with activated receptor tyrosine kinases (RTK), and a p110 catalytic subunit, which triggers production of second messengers and subsequent downstream signaling. Although the p110α and p110β isoforms are highly homologous, recent studies suggest that they may have distinct, tissue-specific functions in RTK-mediated oncogenic transformation. To investigate this possibility, Utermark and colleagues examined the effect of genetic ablation of each isoform on mammary tumorigenesis. Heterozygosity for p110α significantly delayed tumor onset and reduced tumor burden in both the polyoma middle T antigen (MT) and HER2/Neu mouse models of breast cancer, suggesting that p110α is necessary for RTK-stimulated mammary tumorigenesis. In contrast, complete loss of p110β enhanced mammary tumor growth and ductal branching in these models. PI3K signaling was reciprocally regulated by these isoforms in isolated mammary tumor cells and normal primary mouse mammary epithelial cells; p110α deficiency diminished phosphorylated AKT levels and lipid kinase activity, whereas p110β deletion led to increased PI3K activity. This negative regulatory effect of p110β can be explained by a model in which p110β competes for receptor binding with the more active p110α isoform, thereby adjusting the level of PI3K signaling. Consistent with this idea, increased association of p110α with activated RTKs was detected in the absence of p110β. Importantly, selective inhibition of p110α reduced MT and Neu-driven signaling and tumor growth. These findings implicate p110α as the principal isoform mediating PI3K signaling in mammary epithelial cells and suggest that specific p110α inhibitors may be effective in treating HER2-positive breast cancer.

Utermark T, Rao T, Cheng H, Wang Q, Lee SH, Wang ZC, et al. The p110α and p110β isoforms of PI3K play divergent roles in mammary gland development and tumorigenesis. Genes Dev 2012;26:1573–86.