title: The mTOR effectors 4EBP1 and S6K2 are frequently coexpressed, and associated with a poor prognosis and endocrine resistance in breast cancer: a retrospective study including patients from the randomised Stockholm tamoxifen trials.
abstract: BACKGROUND
  mTOR and its downstream effectors the 4E-binding protein 1 (4EBP1) and the p70 ribosomal S6 kinases (S6K1 and S6K2) are frequently upregulated in breast cancer, and assumed to be driving forces in tumourigenesis, in close connection with oestrogen receptor (ER) networks. Here, we investigated these factors as clinical markers in five different cohorts of breast cancer patients.
  
  
  METHODS
  The prognostic significance of 4EBP1, S6K1 and S6K2 mRNA expression was assessed with real-time PCR in 93 tumours from the treatment randomised Stockholm trials, encompassing postmenopausal patients enrolled between 1976 and 1990. Three publicly available breast cancer cohorts were used to confirm the results. Furthermore, the predictive values of 4EBP1 and p4EBP1_S65 protein expression for both prognosis and endocrine treatment benefit were assessed by immunohistochemical analysis of 912 node-negative breast cancers from the Stockholm trials.
  
  
  RESULTS
  S6K2 and 4EBP1 mRNA expression levels showed significant correlation and were associated with a poor outcome in all cohorts investigated. 4EBP1 protein was confirmed as an independent prognostic factor, especially in progesterone receptor (PgR)-expressing cancers. 4EBP1 protein expression was also associated with a poor response to endocrine treatment in the ER/PgR positive group. Cross-talk to genomic as well as non-genomic ER/PgR signalling may be involved and the results further support a combination of ER and mTOR signalling targeted therapies.
  
  
  CONCLUSIONS
  This study suggests S6K2 and 4EBP1 as important factors for breast tumourigenesis, interplaying with hormone receptor signalling. We propose S6K2 and 4EBP1 as new potential clinical markers for prognosis and endocrine therapy response in breast cancer.
authors.forename: Elin
authors.initials: E
authors.lastname: Karlsson
authors.forename: Gizeh
authors.initials: G
authors.lastname: Pérez-Tenorio
authors.forename: Risul
authors.initials: R
authors.lastname: Amin
authors.forename: Josefine
authors.initials: J
authors.lastname: Bostner
authors.forename: Lambert
authors.initials: L
authors.lastname: Skoog
authors.forename: Tommy
authors.initials: T
authors.lastname: Fornander
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Sgroi
authors.forename: Bo
authors.initials: B
authors.lastname: Nordenskjöld
authors.forename: Anna-Lotta
authors.initials: AL
authors.lastname: Hallbeck
authors.forename: Olle
authors.initials: O
authors.lastname: Stål
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D018931:Antineoplastic Agents, Hormonal; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality; D018797:Cell Cycle Proteins; D019008:Drug Resistance, Neoplasm; D005260:Female; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D063868:Patient Outcome Assessment; D010750:Phosphoproteins / Q000235:genetics*; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D012008:Recurrence; D012189:Retrospective Studies; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013629:Tamoxifen / Q000627:therapeutic use
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018931:Antineoplastic Agents, Hormonal; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D010750:Phosphoproteins; D012333:RNA, Messenger; D013629:Tamoxifen; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases