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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  < 10 −10 ). pAKT pathway activation was significantly associated with better outcomes (multivariable HR, 0.79; 95%CI, 0.74–0.85;  p  = 2.5 × 10 −10 ) and  PIK3CA  mutations ( p  = 0.0001) whereas p-mTOR pathway activation showed worse outcomes (multivariable HR,1.1; 95%CI, 1.1–1.2;  p  = 9.9 × 10 −4 ) and associated with  p53  mutations ( p  = 0.04). 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.

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