title: Class III β-tubulin overexpression in ovarian clear cell and serous carcinoma as a maker for poor overall survival after platinum/taxane chemotherapy and sensitivity to patupilone.
abstract: OBJECTIVE
  Clear cell carcinoma of the ovary is a distinct subtype of epithelial cancer associated with chemoresistance and poor outcome compared with serous papillary carcinomas. Resistance to paclitaxel has been linked to serous papillary overexpression of class III β-tubulin in several human cancers but inadequately characterized among clear cell carcinoma of the ovary. Chemoresistance has also been variably linked to the drug efflux pump p-glycoprotein. Epothilones are microtubule-stabilizing agents with putative activity in paclitaxel-resistant malignancies. In this study, we clarify the relationship between class III β-tubulin and p-glycoprotein expression in clear cell carcinoma of the ovary, clinical outcome, and in vitro responsiveness to patupilone and paclitaxel.
  
  
  METHODS
  Class III β-tubulin and p-glycoprotein were quantified by real time polymerase chain reaction in 61 fresh-frozen tissue samples and 11 cell lines. Expression by polymerase chain reaction was correlated with immunohistochemistry and overall survival. IC50 was determined using viability/metabolic assays. Impact of class III β-tubulin down-regulation on IC50 was assessed with small interfering RNAs.
  
  
  RESULTS
  Clear cell carcinoma of the ovary overexpressed class III β-tubulin and p-glycoprotein relative to serous papillary carcinomas carcinomas in fresh-frozen tissues and cell lines. Class III β-tubulin immunohistochemistry reflected real time polymerase chain reaction results and overexpression stratified patients by overall survival. P-glycoprotein correlated with in vitro paclitaxel resistance, but not clinical outcome. Clear cell carcinoma of the ovary were exquisitely sensitive to patupilone in a manner that correlated with class III β-tubulin expression.
  
  
  CONCLUSIONS
  Class III β-tubulin overexpression in clear cell carcinoma of the ovary discriminates poor prognosis, serves as a marker for sensitivity to patupilone, and may contribute to paclitaxel resistance. Immunohistochemistry reliably identifies tumors with overexpression of class III β-tubulin, and accordingly a subset of individuals likely to respond to patupilone.
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT.
authors.forename: Dana M
authors.initials: DM
authors.lastname: Roque
authors.forename: Stefania
authors.initials: S
authors.lastname: Bellone
authors.forename: Natalia
authors.initials: N
authors.lastname: Buza
authors.forename: Chiara
authors.initials: C
authors.lastname: Romani
authors.forename: Emiliano
authors.initials: E
authors.lastname: Cocco
authors.forename: Eliana
authors.initials: E
authors.lastname: Bignotti
authors.forename: Antonella
authors.initials: A
authors.lastname: Ravaggi
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Rutherford
authors.forename: Peter E
authors.initials: PE
authors.lastname: Schwartz
authors.forename: Sergio
authors.initials: S
authors.lastname: Pecorelli
authors.forename: Alessandro D
authors.initials: AD
authors.lastname: Santin
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002460:Cell Line; D018284:Cystadenocarcinoma, Serous / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D034261:Epothilones / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008870:Microtubules / Q000187:drug effects; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality; D017239:Paclitaxel / Q000494:pharmacology*; D011379:Prognosis; D060888:Real-Time Polymerase Chain Reaction; D043823:Taxoids / Q000494:pharmacology; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D034261:Epothilones; D043823:Taxoids; D014404:Tubulin; D050257:Tubulin Modulators; D017239:Paclitaxel
keywords: class III β-tubulin; epothilone; ovarian clear cell carcinoma; ovarian serous carcinoma; paclitaxel resistance; prognostic marker