Class III β-tubulin overexpression in ovarian clear cell and serous carcinoma as a marker for poor overall survival after platinum/taxane chemotherapy and sensitivity to patupilone

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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 paclitaxelresistant 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. IC 50 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. © 2013 Mosby, Inc. All rights reserved.

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Roque, D. M., Bellone, S., Buza, N., Romani, C., Cocco, E., Bignotti, E., … Santin, A. D. (2013). Class III β-tubulin overexpression in ovarian clear cell and serous carcinoma as a marker for poor overall survival after platinum/taxane chemotherapy and sensitivity to patupilone. American Journal of Obstetrics and Gynecology, 209(1), 62.e1-62.e9. https://doi.org/10.1016/j.ajog.2013.04.017

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