npj Breast Cancer ( IF 5.9 ) Pub Date : 2019-01-31 , DOI: 10.1038/s41523-019-0102-1 Amir Sonnenblick , David Venet , Sylvain Brohée , Noam Pondé , Christos Sotiriou
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.
中文翻译:
与p-mTOR途径激活相反,pAKT途径激活与PIK3CA突变相关,并且在管腔乳腺癌中预后良好
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。