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

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.

Author information

1
Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT.

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

PMID:
23583215
DOI:
10.1016/j.ajog.2013.04.017
[Indexed for MEDLINE]

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