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 < 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.
Highlights
The phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR-signaling pathway mediates key cellular functions, including growth, proliferation, and survival and is frequently involved in carcinogenesis, tumor progression, and metastases.[1]
Numerous studies have focused on the PI3K/AKT/mTOR pathway in estrogen receptor positive (ER-positive) breast cancer (BC) and have shown that PIK3CA mutations are frequent, that the PI3K/AKT/mTORsignaling pathway is often dysregulated and that both correlate with worse clinical outcomes.[2,3,4]
The PI3K/AKT/mTOR pathway is usually considered as a linear signal transduction pathway in BC, in the ER-positive disease, we have previously shown that PIK3CA mutations were associated with relatively low mTOR complex 1 (mTORC1) functional output and with good outcomes in patients who received adjuvant tamoxifen monotherapy.[4]
Summary
The phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR-signaling pathway mediates key cellular functions, including growth, proliferation, and survival and is frequently involved in carcinogenesis, tumor progression, and metastases.[1]. While AKT is activated by phospholipid binding and activation loop phosphorylation at Threonine[308] by PDK1 and by phosphorylation within the carboxy terminus at Serine[473], mTOR is phosphorylated at Serine2448 via the PI3K-signaling pathway.[7] AKT activates the mTOR complex 1 (mTORC1) which in addition to mTOR contains mLST8, PRAS40, and RAPTOR.[8] This activation involves phosphorylation of tuberous sclerosis complex 2 (TSC2), which blocks the ability of TSC2 to act as a GTPase-activating protein, thereby allowing accumulation of Rheb-GTP and mTORC1 activation. AKT can activate mTORC1 by PRAS40 phosphorylation, thereby relieving the PRAS40-mediated inhibition of mTORC1.9
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