title: Tubulin-β-III overexpression by uterine serous carcinomas is a marker for poor overall survival after platinum/taxane chemotherapy and sensitivity to epothilones.
abstract: BACKGROUND
  Uterine serous carcinoma (USC) is a subtype of endometrial cancer associated with chemoresistance and poor outcome. Overexpression of tubulin-β-III and p-glycoprotein has been linked to paclitaxel resistance in many cancers but has been undercharacterized among USCs. Epothilones have demonstrated activity in certain paclitaxel-resistant malignancies. In this study, relationships are clarified, in USCs relative to ovarian serous carcinomas (OSCs), between tubulin-β-III and p-glycoprotein expression, clinical outcome, and in vitro chemoresponsiveness to epothilone B, ixabepilone, and paclitaxel.
  
  
  METHODS
  Tubulin-β-III and p-glycoprotein were quantified by real-time polymerase chain reaction in 48 fresh-frozen tissue samples and 13 cell lines. Copy number was correlated with immunohistochemistry and overall survival. Median inhibitory concentration (IC50 ) was determined using viability and metabolic assays. Impact of tubulin-β-III knockdown on IC50 was assessed with small interfering RNAs.
  
  
  RESULTS
  USC overexpressed tubulin-β-III but not p-glycoprotein relative to OSC in both fresh-frozen tissues (552.9 ± 106.7 versus 202.0 ± 43.99, P = .01) and cell lines (1701.0 ± 376.4 versus 645.1 ± 157.9, P = .02). Tubulin-β-III immunohistochemistry reflected quantitative real-time polymerase chain reaction copy number and overexpression stratified patients by overall survival (copy number ≤ 400: 615 days; copy number > 400: 165 days, P = .049); p-glycoprotein did not predict clinical outcome. USCs remained exquisitely sensitive to patupilone in vitro despite tubulin-β-III overexpression (IC50,USC 0.245 ± 0.11 nM versus IC50,OSC 1.01 ± 0.13 nM, P = .006).
  
  
  CONCLUSIONS
  Tubulin-β-III overexpression in USCs discriminates poor prognosis, serves as a marker for sensitivity to epothilones, and may contribute to paclitaxel resistance. Immunohistochemistry reliably identifies tumors with overexpression of tubulin-β-III, and a subset of individuals likely to respond to patupilone and ixabepilone. Epothilones warrant clinical investigation for treatment of USCs.
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Dana M
authors.initials: DM
authors.lastname: Roque
authors.forename: Stefania
authors.initials: S
authors.lastname: Bellone
authors.forename: Diana P
authors.initials: DP
authors.lastname: English
authors.forename: Natalia
authors.initials: N
authors.lastname: Buza
authors.forename: Emiliano
authors.initials: E
authors.lastname: Cocco
authors.forename: Sara
authors.initials: S
authors.lastname: Gasparrini
authors.forename: Ileana
authors.initials: I
authors.lastname: Bortolomai
authors.forename: Elena
authors.initials: E
authors.lastname: Ratner
authors.forename: Dan-Arin
authors.initials: DA
authors.lastname: Silasi
authors.forename: Masoud
authors.initials: M
authors.lastname: Azodi
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Rutherford
authors.forename: Peter E
authors.initials: PE
authors.lastname: Schwartz
authors.forename: Alessandro D
authors.initials: AD
authors.lastname: Santin
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D018284:Cystadenocarcinoma, Serous / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D019008:Drug Resistance, Neoplasm; D034261:Epothilones / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009367:Neoplasm Staging; D017239:Paclitaxel / Q000008:administration & dosage; D017671:Platinum Compounds / Q000008:administration & dosage; D011237:Predictive Value of Tests; D011379:Prognosis; D060888:Real-Time Polymerase Chain Reaction; D014404:Tubulin / Q000378:metabolism*; D050257:Tubulin Modulators / Q000008:administration & dosage / Q000494:pharmacology*; D015854:Up-Regulation; D014594:Uterine Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D034261:Epothilones; D017671:Platinum Compounds; C498585:TUBB3 protein, human; D014404:Tubulin; D050257:Tubulin Modulators; C430592:ixabepilone; D017239:Paclitaxel; C093788:epothilone B
keywords: epothilone; ovarian serous carcinoma; paclitaxel resistance; tubulin-β-III; uterine serous carcinoma