AKT activation predicts outcome in breast cancer patients treated with tamoxifen

Abstract

Oestrogen receptor (ERalpha) expression is a strong predictor of response to endocrine therapy. The PI3K/AKT/mTOR signal transduction pathway has been implicated in endocrine resistance in vitro. The present study was carried out to test the hypothesis that AKT activation mediates tamoxifen resistance in clinical breast cancer. Immunohistochemistry (IHC) using AKT1-3, pan-AKT, pAKT (Thr-308), pAKT (Ser-473), pER (Ser-167), and pHER2 antibodies was performed on 402 ERalpha-positive breast carcinomas from patients treated with tamoxifen. High pAKT (Ser-473) activity (p = 0.0406) and low AKT2 expression (p = 0.0115) alone, or in combination [high pAKT (Ser-473)/low AKT2; 'high-risk' patient group] (p = 0.0014), predicted decreased overall survival in tamoxifen-treated patients with ERalpha-positive breast cancers. There was no significant association between tumour levels of AKT expression or activity and disease-free survival (DFS); however, the 'high-risk' patient group was significantly more likely to relapse (p = 0.0491). During tamoxifen treatment, neither AKT2 nor pAKT predicted DFS. Finally, activation of AKT, via phosphorylation, was linked to activation of both HER2 and ERalpha in this patient cohort. The data presented here show that the PI3K/AKT/mTOR pathway is associated with relapse and death in ERalpha-positive breast cancer patients treated with tamoxifen, supporting in vitro evidence that AKT mediates tamoxifen resistance. Patients with a 'high-risk' expression profile were at increased risk of death (hazard ratio 3.22, p = 0.002) relative to 'low-risk' patients, highlighting the potential that tumour profiling, with multiple IHC markers predictive of therapeutic response, may improve patient selection for endocrine therapies, eg tamoxifen or aromatase inhibitor-based treatments.

A gene transcription signature of the Akt/mTOR pathway in clinical breast tumors

“…These findings indicate that mTOR is an essential therapeutic target of the Akt pathway. It is notable that Akt has been previously thought to be involved in development of resistance to hormone therapy (Kirkegaard et al, 2005;Tokunaga et al, 2006). The association of the Akt-mTOR genes with poor prognosis was found in some but not all patient data sets examined, although it is not readily apparent that this reflects the different treatment regimens being represented among the various tumor profiling studies.…”

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

“…157 In addition, approximately 5% of breast cancers may harbour activating mutations in AKT. 158 The fact that strong immunostaining for Akt has been associated with a poor prognosis in breast cancer patients independent of adjuvant therapy [159][160][161] indicates a general prognostic role for activation of the PI3K/Akt system in breast cancer. Notably, experimental evidence has linked activation of the Akt/mTOR pathway to a number of biological processes; overexpressing Akt has been shown to enhance lymphangiogenesis and confer resistance to cyclophosphamide as well as doxorubicin in murine models, 162 effects that are reversed by blocking Akt's downstream effector mTOR by rapamycin.…”

Improved survival related to changes in endometrial cancer treatment, a 30-year population based perspective

“…118 For AKT immunohistochemical staining, no correlations with clinico-pathological factors and survival have been reported from several studies investigating breast-, gastric-and bronchial cancers. [205][206][207] Our study of endometrial carcinomas adds to this general impression that AKT is not valuable as a cancer prognosticator. Also, we find that AKT staining is not related to activation of the PI3Kinase signalling level at the mRNA level (Paper I).…”