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.

许多研究都集中在雌激素受体阳性（ER）乳腺癌（BC）中的PI3K / AKT / mTOR途径作为线性信号转导途径，并报道了其与较差的临床结果的关联。我们开发了分别反映磷酸化Serine473-AKT（pAKT）和磷酸化Serine2448-mTOR（p-mTOR）表达水平的基因标志，捕获了它们相应的途径激活水平。我们的分析显示，pAKT途径激活与A BC腔相关，而p-mTOR途径激活与B BC腔更相关（Kruskal–Wallis测试p  <10 ^-10）。pAKT途径激活与更好的结局显着相关（多变量HR，0.79； 95％CI，0.74-0.85；p  = 2.5×10^-10）和PIK3CA突变（p  = 0.0001），而p-mTOR途径激活显示出较差的结果（多变量HR，1.1; 95％CI，1.1-1.2; p  = 9.9×10 ^-4），并与p53突变相关（p  = 0.04）。总之，我们的数据表明pAKT和p-mTOR途径的激活对预后有不同的影响，并表明它们在管腔型乳腺癌中不是线性连接的。