Tubulin--III overexpression by uterine serous carcinomas is a marker for poor overall survival after platinum/taxane chemotherapy and sensitivity to epothilones

BACKGROUND Uterine serous carcinoma (USC) is a subtype of endometrial cancer associated with chemoresistance and poor outcome. Overexpression of tubulin--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--III and p-glycoprotein expression, clinical outcome, and in vitro chemoresponsiveness to epothilone B, ixabepilone, and paclitaxel. METHODS Tubulin--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--III knockdown on IC50 was assessed with small interfering RNAs. RESULTS USC overexpressed tubulin--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--III immunohistochemistry reflected quantitative real-time polymerase chain reaction copy number and overexpression stratified patients by overall survival (copy number400: 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--III overexpression (IC50,USC 0.245 +/- 0.11 nM versus IC50,OSC 1.01 +/- 0.13 nM, P=.006). CONCLUSIONS Tubulin--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--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. (c) 2013 American Cancer Society.