Tubulin-β-III overexpression by uterine serous carcinomas is a marker for poor overall survival after platinum/taxane chemotherapy and sensitivity to epothilones
Article first published online: 12 APR 2013
© 2013 American Cancer Society
Volume 119, Issue 14, pages 2582–2592, 15 July 2013
How to Cite
Roque, D. M., Bellone, S., English, D. P., Buza, N., Cocco, E., Gasparrini, S., Bortolomai, I., Ratner, E., Silasi, D.-A., Azodi, M., Rutherford, T. J., Schwartz, P. E. and Santin, A. D. (2013), Tubulin-β-III overexpression by uterine serous carcinomas is a marker for poor overall survival after platinum/taxane chemotherapy and sensitivity to epothilones. Cancer, 119: 2582–2592. doi: 10.1002/cncr.28017
- Issue published online: 1 JUL 2013
- Article first published online: 12 APR 2013
- Manuscript Accepted: 2 JAN 2013
- Manuscript Revised: 15 DEC 2012
- Manuscript Received: 27 SEP 2012
- uterine serous carcinoma;
- paclitaxel resistance;
- ovarian serous carcinoma
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.
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.
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).
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. Cancer 2013;119:2582–2592. © 2013 American Cancer Society.