pAKT pathway activation is associated with PIK3CA mutations and good prognosis in luminal breast cancer in contrast to p-mTOR pathway activation

Abstract

Numerous studies have focused on the PI3K/AKT/mTOR pathway in estrogen receptor positive (ER) breast cancer (BC), as a linear signal transduction pathway and reported its association with worse clinical outcomes. We developed gene signatures that reflect the level of expression of phosphorylated-Serine473-AKT (pAKT) and phosphorylated-Serine2448-mTOR (p-mTOR) separately, capturing their corresponding level of pathway activation. Our analysis revealed that the pAKT pathway activation was associated with luminal A BC while the p-mTOR pathway activation was more associated with luminal B BC (Kruskal–Wallis test p\u2009<\u200910−10). pAKT pathway activation was significantly associated with better outcomes (multivariable HR, 0.79; 95%CI, 0.74–0.85; p\u2009=\u20092.5\u2009×\u200910−10) and PIK3CA mutations (p\u2009=\u20090.0001) whereas p-mTOR pathway activation showed worse outcomes (multivariable HR,1.1; 95%CI, 1.1–1.2; p\u2009=\u20099.9\u2009×\u200910−4) and associated with p53 mutations (p\u2009=\u20090.04). in conclusion, our data show that pAKT and p-mTOR pathway activation have differing impact on prognosis and suggest that they are not linearly connected in luminal breast cancers.Molecular signaling: Two components of same pathway have divergent effectsOne of the key signaling pathways involved in regulating cancer cell growth and survival is not linearly connected in luminal breast cancers, as researchers had long assumed. A team led by Amir Sonnenblick from Tel Aviv University, Israel, and Christos Sotiriou from Institut Jules Bordet, Belgium, studied tumors with elevated expression of two different proteins in the PI3K/AKT/mTOR pathway. They showed that tumors with activated AKT had distinct gene expression profiles from tumors with activated mTOR. What’s more, patients with AKT activation had better outcomes on average and were more likely to carry mutations in the oncogene PIK3CA, whereas patients with mTOR activation tended to relapse sooner and were more likely to carry mutations in the tumor suppressor p53. The findings suggest that doctors should look closely at PI3K/AKT/mTOR signaling activation when personalizing treatment decisions.