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

Am J Obstet Gynecol. 2013 Jul;209(1):62.e1-9. doi: 10.1016/j.ajog.2013.04.017. Epub 2013 Apr 10.

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.

Study design: 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.

Conclusion: 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.

Keywords: class III β-tubulin; epothilone; ovarian clear cell carcinoma; ovarian serous carcinoma; paclitaxel resistance; prognostic marker.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Antineoplastic Agents / pharmacology*
  • Cell Line
  • Cystadenocarcinoma, Serous* / drug therapy
  • Cystadenocarcinoma, Serous* / metabolism
  • Cystadenocarcinoma, Serous* / mortality
  • Dose-Response Relationship, Drug
  • Down-Regulation
  • Drug Resistance, Neoplasm / drug effects
  • Epothilones / pharmacology*
  • Female
  • Humans
  • Immunohistochemistry
  • Kaplan-Meier Estimate
  • Microtubules / drug effects
  • Neoplasms, Glandular and Epithelial / drug therapy*
  • Neoplasms, Glandular and Epithelial / metabolism
  • Neoplasms, Glandular and Epithelial / mortality
  • Ovarian Neoplasms* / drug therapy
  • Ovarian Neoplasms* / metabolism
  • Ovarian Neoplasms* / mortality
  • Paclitaxel / pharmacology*
  • Prognosis
  • Real-Time Polymerase Chain Reaction
  • Taxoids / pharmacology
  • Tubulin / metabolism
  • Tubulin Modulators / pharmacology*

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antineoplastic Agents
  • Epothilones
  • Taxoids
  • Tubulin
  • Tubulin Modulators
  • Paclitaxel