title: S6 kinase signaling: tamoxifen response and prognostic indication in two breast cancer cohorts.
abstract: Detection of signals in the mammalian target of rapamycin (mTOR) and the estrogen receptor (ER) pathways may be a future clinical tool for the prediction of adjuvant treatment response in primary breast cancer. Using immunohistological staining, we investigated the value of the mTOR targets p70-S6 kinase (S6K) 1 and 2 as biomarkers for tamoxifen benefit in two independent clinical trials comparing adjuvant tamoxifen with no tamoxifen or 5 years versus 2 years of tamoxifen treatment. In addition, the prognostic value of the S6Ks was evaluated. We found that S6K1 correlated with proliferation, HER2 status, and cytoplasmic AKT activity, whereas high protein expression levels of S6K2 and phosphorylated (p) S6K were more common in ER-positive, and low-proliferative tumors with pAKT-s473 localized to the nucelus. Nuclear accumulation of S6K1 was indicative of a reduced tamoxifen effect (hazard ratio (HR): 1.07, 95% CI: 0.53-2.81, P=0.84), compared with a significant benefit from tamoxifen treatment in patients without tumor S6K1 nuclear accumulation (HR: 0.42, 95% CI: 0.29-0.62, P<0.00001). Also S6K1 and S6K2 activation, indicated by pS6K-t389 expression, was associated with low benefit from tamoxifen (HR: 0.97, 95% CI: 0.50-1.87, P=0.92). In addition, high protein expression of S6K1, independent of localization, predicted worse prognosis in a multivariate analysis, P=0.00041 (cytoplasm), P=0.016 (nucleus). In conclusion, the mTOR-activated kinases S6K1 and S6K2 interfere with proliferation and response to tamoxifen. Monitoring their activity and intracellular localization may provide biomarkers for breast cancer treatment, allowing the identification of a group of patients less likely to benefit from tamoxifen and thus in need of an alternative or additional targeted treatment.
authors.affiliation: Department of Clinical and Experimental MedicineDepartment of OncologyDepartment of Clinical and Experimental MedicineDivision of Dermatology, Linköping University, SE-58185 Linköping, SwedenDepartment of OncologyKarolinska University Hospital, Karolinska Institute, SE-17176 Stockholm, Sweden Josefine.Bostner@liu.se.
authors.forename: Josefine
authors.initials: J
authors.lastname: Bostner
authors.affiliation: Department of Clinical and Experimental MedicineDepartment of OncologyDepartment of Clinical and Experimental MedicineDivision of Dermatology, Linköping University, SE-58185 Linköping, SwedenDepartment of OncologyKarolinska University Hospital, Karolinska Institute, SE-17176 Stockholm, Sweden.
authors.forename: Elin
authors.initials: E
authors.lastname: Karlsson
authors.affiliation: Department of Clinical and Experimental MedicineDepartment of OncologyDepartment of Clinical and Experimental MedicineDivision of Dermatology, Linköping University, SE-58185 Linköping, SwedenDepartment of OncologyKarolinska University Hospital, Karolinska Institute, SE-17176 Stockholm, Sweden.
authors.forename: Cecilia Bivik
authors.initials: CB
authors.lastname: Eding
authors.affiliation: Department of Clinical and Experimental MedicineDepartment of OncologyDepartment of Clinical and Experimental MedicineDivision of Dermatology, Linköping University, SE-58185 Linköping, SwedenDepartment of OncologyKarolinska University Hospital, Karolinska Institute, SE-17176 Stockholm, Sweden.
authors.forename: Gizeh
authors.initials: G
authors.lastname: Perez-Tenorio
authors.affiliation: Department of Clinical and Experimental MedicineDepartment of OncologyDepartment of Clinical and Experimental MedicineDivision of Dermatology, Linköping University, SE-58185 Linköping, SwedenDepartment of OncologyKarolinska University Hospital, Karolinska Institute, SE-17176 Stockholm, Sweden.
authors.forename: Hanna
authors.initials: H
authors.lastname: Franzén
authors.affiliation: Department of Clinical and Experimental MedicineDepartment of OncologyDepartment of Clinical and Experimental MedicineDivision of Dermatology, Linköping University, SE-58185 Linköping, SwedenDepartment of OncologyKarolinska University Hospital, Karolinska Institute, SE-17176 Stockholm, Sweden.
authors.forename: Aelita
authors.initials: A
authors.lastname: Konstantinell
authors.affiliation: Department of Clinical and Experimental MedicineDepartment of OncologyDepartment of Clinical and Experimental MedicineDivision of Dermatology, Linköping University, SE-58185 Linköping, SwedenDepartment of OncologyKarolinska University Hospital, Karolinska Institute, SE-17176 Stockholm, Sweden.
authors.forename: Tommy
authors.initials: T
authors.lastname: Fornander
authors.affiliation: Department of Clinical and Experimental MedicineDepartment of OncologyDepartment of Clinical and Experimental MedicineDivision of Dermatology, Linköping University, SE-58185 Linköping, SwedenDepartment of OncologyKarolinska University Hospital, Karolinska Institute, SE-17176 Stockholm, Sweden.
authors.forename: Bo
authors.initials: B
authors.lastname: Nordenskjöld
authors.affiliation: Department of Clinical and Experimental MedicineDepartment of OncologyDepartment of Clinical and Experimental MedicineDivision of Dermatology, Linköping University, SE-58185 Linköping, SwedenDepartment of OncologyKarolinska University Hospital, Karolinska Institute, SE-17176 Stockholm, Sweden.
authors.forename: Olle
authors.initials: O
authors.lastname: Stål
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D045744:Cell Line, Tumor; D015331:Cohort Studies; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007527:Isoenzymes; D011379:Prognosis; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013629:Tamoxifen / Q000008:administration & dosage*; D014162:Transfection
chemical_list: D018931:Antineoplastic Agents, Hormonal; D007527:Isoenzymes; D013629:Tamoxifen; D038762:Ribosomal Protein S6 Kinases, 70-kDa; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1
keywords: AKT; S6K1; S6K2; endocrine treatment; estrogen receptor; mTOR; pS6K