Premium
AKT activation predicts outcome in breast cancer patients treated with tamoxifen
Author(s) -
Kirkegaard Tove,
Witton Caroline J,
McGlynn Liane M,
Tovey Sian M,
Dunne Barbara,
Lyon Alison,
Bartlett John MS
Publication year - 2005
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.1829
Subject(s) - tamoxifen , breast cancer , medicine , akt2 , protein kinase b , oncology , pi3k/akt/mtor pathway , estrogen receptor , cancer research , hazard ratio , cancer , akt1 , endocrinology , signal transduction , biology , confidence interval , biochemistry
Abstract Oestrogen receptor (ERα) 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 ERα‐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 ERα‐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 ERα in this patient cohort. The data presented here show that the PI3K/AKT/mTOR pathway is associated with relapse and death in ERα‐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. Copyright © 2005 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.