title: 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.
authors.affiliation: Endocrine Cancer Group, Division of Cancer Sciences and Molecular Pathology, Department of Surgery, Glasgow Royal Infirmary, Glasgow G31 2ER, UK.
authors.forename: Tove
authors.initials: T
authors.lastname: Kirkegaard
authors.forename: Caroline J
authors.initials: CJ
authors.lastname: Witton
authors.forename: Liane M
authors.initials: LM
authors.lastname: McGlynn
authors.forename: Sian M
authors.initials: SM
authors.lastname: Tovey
authors.forename: Barbara
authors.initials: B
authors.lastname: Dunne
authors.forename: Alison
authors.initials: A
authors.lastname: Lyon
authors.forename: John M S
authors.initials: JM
authors.lastname: Bartlett
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004847:Epithelial Cells / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D009361:Neoplasm Invasiveness / Q000473:pathology; D009363:Neoplasm Proteins / Q000032:analysis; D017346:Protein Serine-Threonine Kinases / Q000032:analysis / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis; D011960:Receptors, Estrogen / Q000032:analysis; D012189:Retrospective Studies; D015398:Signal Transduction; D016019:Survival Analysis; D013629:Tamoxifen / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D013629:Tamoxifen; C494918:AKT1 protein, human; C494921:AKT2 protein, human