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AKT activation predicts outcome in breast cancer patients treated with tamoxifen
- Source :
- The Journal of pathology. 207(2)
- Publication Year :
- 2005
-
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.
- Subjects :
- Oncology
medicine.medical_specialty
Antineoplastic Agents, Hormonal
medicine.drug_class
Receptor, ErbB-2
AKT2
Breast Neoplasms
Protein Serine-Threonine Kinases
Pathology and Forensic Medicine
Breast cancer
Internal medicine
Proto-Oncogene Proteins
medicine
Biomarkers, Tumor
Humans
Neoplasm Invasiveness
skin and connective tissue diseases
Protein kinase B
Survival analysis
PI3K/AKT/mTOR pathway
Retrospective Studies
Aromatase inhibitor
business.industry
Epithelial Cells
medicine.disease
Immunohistochemistry
Survival Analysis
Neoplasm Proteins
Tamoxifen
Endocrinology
Treatment Outcome
Receptors, Estrogen
Female
business
Proto-Oncogene Proteins c-akt
hormones, hormone substitutes, and hormone antagonists
medicine.drug
Signal Transduction
Subjects
Details
- ISSN :
- 00223417
- Volume :
- 207
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- The Journal of pathology
- Accession number :
- edsair.doi.dedup.....5a0c259d23120f2546abd3dfb1ca3cab