Activation of Akt, mTOR, and the estrogen receptor as a signature to predict tamoxifen treatment benefit

Abstract

The frequent alterations of the PI3K/Akt/mTOR-growth signaling pathway are proposed mechanisms for resistance to endocrine therapy in breast cancer, partly through regulation of estrogen receptor α (ER) activity. Reliable biomarkers for treatment prediction are required for improved individualized treatment. We performed a retrospective immunohistochemical analysis of primary tumors from 912 postmenopausal patients with node-negative breast cancer, randomized to either tamoxifen or no adjuvant treatment. Phosphorylated (p) Akt-serine (s) 473, p-mTOR-s2448, and ER phosphorylations-s167 and -s305 were evaluated as potential biomarkers of prognosis and tamoxifen treatment efficacy. High expression of p-mTOR indicated a reduced response to tamoxifen, most pronounced in the ER+/progesterone receptor (PgR) + subgroup (tamoxifen vs. no tamoxifen: hazard ratio (HR), 0.86; 95 % confidence interval (CI), 0.31–2.38; P = 0.78), whereas low p-mTOR expression predicted tamoxifen benefit (HR, 0.29; 95 % CI, 0.18–0.49; P = 0.000002). In addition, nuclear p-Akt-s473 as well as p-ER at -s167 and/or -s305 showed interaction with tamoxifen efficacy with borderline statistical significance. A combination score of positive pathway markers including p-Akt, p-mTOR, and p-ER showed significant association with tamoxifen benefit (test for interaction; P = 0.029). Cross-talk between growth signaling pathways and ER-signaling has been proposed to affect tamoxifen response in hormone receptor-positive breast cancer. The results support this hypothesis, as an overactive pathway was significantly associated with reduced response to tamoxifen. A clinical pre-treatment test for cross-talk markers would be a step toward individualized adjuvant endocrine treatment with or without the addition of PI3K/Akt/mTOR pathway inhibitors.Electronic supplementary materialThe online version of this article (doi:10.1007/s10549-012-2376-y) contains supplementary material, which is available to authorized users.

Loss of protein tyrosine phosphatase, non-receptor type 2 is associated with activation of AKT and tamoxifen resistance in breast cancer

“…Alterations in the PI3K/AKT pathway, mainly PIK3CA mutations, have been shown most frequent in the luminal subtypes, suggesting a crosstalk between ER and PI3K/AKT [3]. Aberrant PI3K/AKT signalling has been connected to poor response to anti-oestrogen therapies in several studies [20,[42][43][44][45][46][47][48][49][50]. In the present study, we showed PTPN2 gene loss as a new potential marker of endocrine resistance.…”

AKT-Induced Tamoxifen Resistance Is Overturned by RRM2 Inhibition

“…Recently, a retrospective immunohistochemical study of primary tumors showed that overactivity of the AKT pathway was significantly associated with a reduced response to tamoxifen therapy (13). In another study, the overexpression of phosphorylated AKT or active AKT (pAKT) was detected in 58% of breast cancer samples, and survival analyses revealed that patients whose tumors were pAKTpositive were more prone to relapse with distant metastases (14).…”

Long-term remission of hormone receptor-positive/HER2-positive metastatic breast cancer due to combined treatment with everolimus/trastuzumab/exemestane: A case report

“…An emerging mechanism of endocrine resistance is the interaction between the PI3K-protein kinase B-mTOR and ER signaling pathways (22)(23)(24). In a previous study involving patients with newly diagnosed breast cancer, neoadjuvant everolimus combined with letrozole improved the clinical response rate and decreased tumor cell viability, compared with letrozole alone (42).…”

“…The interaction between the phosphoinositide 3-kinase (PI3K)-protein kinase B-mammalian target of rapamycin (mTOR) and ER signaling pathways is an additional emerging mechanism of endocrine resistance (22)(23)(24). mTOR is a downstream target in the HER2 signaling pathway and is associated with the activity of the ER signaling pathway.…”