title: High phospho-Stathmin(Serine38) expression identifies aggressive endometrial cancer and suggests an association with PI3K inhibition.
abstract: OBJECTIVE
  High Stathmin expression has recently been associated with clinical progress in endometrial cancers. Stathmin protein activity is modulated by phosphorylation, and the Serine38 site is one of four Stathmin phospho-sites. The presence and significance of pStathmin(S38) is largely unknown in human cancers, and we here examined the associations between this marker and tumor cell proliferation, clinicopathologic phenotype, and survival impact in endometrial cancer. A relationship with possible treatment targets was explored by integrated analysis of transcriptional alterations.
  
  
  METHODS
  Primary endometrial cancers from two independent patient series (n = 518/n = 286) were analyzed. Biomarkers were assessed by immunohistochemistry, FISH, flow cytometry, DNA oligonucleotide microarray, single-nucleotide polymorphism array, and Sanger sequencing, and related to clinicopathologic annotations and follow-up information.
  
  
  RESULTS
  High pStathmin(S38) level was associated with poor prognosis, independent of other features, and correlated to increased tumor cell proliferation as well as high Stathmin levels. On the basis of transcriptional differences between high/low pStathmin(S38) tumors, phosphoinositide 3-kinase (PI3K)/mTOR/HSP90 were suggested as possible targets in pStathmin(S38)-high cases. High pStathmin(S38) was associated with several PI3K pathway alterations: amplification of the 3q26 region, increased PIK3CA copy number (FISH) and a PI3K activation score (all P < 0.05).
  
  
  CONCLUSIONS
  High pStathmin(S38) is a novel biomarker of increased tumor cell proliferation and impaired prognosis as reported here for independent cohorts of endometrial cancer and not previously shown in human cancer. Our data support a rationale for further studies exploring effects of drugs inhibiting the PI3K signaling pathway in pStathmin(S38)-high endometrial cancer, including a potential value of pStathmin(S38) in predicting response to PI3K/mTOR/HSP90 inhibitors.
authors.affiliation: Department of Obstetrics and Gynecology, Haukeland University Hospital, University of Bergen, Bergen, Norway. elisabeth.wik@med.uib.no
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Wik
authors.forename: Even
authors.initials: E
authors.lastname: Birkeland
authors.forename: Jone
authors.initials: J
authors.lastname: Trovik
authors.forename: Henrica M J
authors.initials: HM
authors.lastname: Werner
authors.forename: Erling A
authors.initials: EA
authors.lastname: Hoivik
authors.forename: Siv
authors.initials: S
authors.lastname: Mjos
authors.forename: Camilla
authors.initials: C
authors.lastname: Krakstad
authors.forename: Kanthida
authors.initials: K
authors.lastname: Kusonmano
authors.forename: Karen
authors.initials: K
authors.lastname: Mauland
authors.forename: Ingunn M
authors.initials: IM
authors.lastname: Stefansson
authors.forename: Frederik
authors.initials: F
authors.lastname: Holst
authors.forename: Kjell
authors.initials: K
authors.lastname: Petersen
authors.forename: Anne M
authors.initials: AM
authors.lastname: Oyan
authors.forename: Ronald
authors.initials: R
authors.lastname: Simon
authors.forename: Karl H
authors.initials: KH
authors.lastname: Kalland
authors.forename: William
authors.initials: W
authors.lastname: Ricketts
authors.forename: Lars A
authors.initials: LA
authors.lastname: Akslen
authors.forename: Helga B
authors.initials: HB
authors.lastname: Salvesen
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002277:Carcinoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D049109:Cell Proliferation; D002893:Chromosomes, Human, Pair 3; D058534:Class I Phosphatidylinositol 3-Kinases; D016889:Endometrial Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D005260:Female; D005784:Gene Amplification; D006801:Humans; D053208:Kaplan-Meier Estimate; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011379:Prognosis; D016016:Proportional Hazards Models; D011499:Protein Processing, Post-Translational; D050777:Stathmin / Q000235:genetics / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D059467:Transcriptome
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins; D050777:Stathmin; D058570:TOR Serine-Threonine Kinases; C493995:STMN1 protein, human; C546842:MTOR protein, human; C484760:PIK3CA protein, human