Tubulin‐β‐III overexpression by uterine serous carcinomas is a marker for poor overall survival after platinum/taxane chemotherapy and sensitivity to epothilones. Issue 14 (12th April 2013)

• Record Type: Journal Article
• Authors: Roque, Dana M.; Bellone, Stefania; English, Diana P.; Buza, Natalia; Cocco, Emiliano; Gasparrini, Sara; Bortolomai, Ileana; Ratner, Elena; Silasi, Dan‐Arin; Azodi, Masoud; Rutherford, Thomas J.; Schwartz, Peter E.; Santin, Alessandro D.
• Is Part Of: Cancer. Volume 119:Issue 14(2013)
• Page Start: 2582
• Page End: 2592
• Publication Date: 2013-04-12
• Subjects: Cancer -- Periodicals; Cancer -- Cytopathology -- Periodicals; 616.99405
• DOI: 10.1002/cncr.28017
• Languages: English
• ISSNs: 0008-543X

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="cncr28017-sec-0001" sec-type="section"> <title>BACKGROUND</title> <p>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.</p> </sec> <sec id="cncr28017-sec-0002" sec-type="section"> <title>METHODS</title> <p>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 (IC<sub>50</sub>) was determined using viability and metabolic assays. Impact of tubulin‐β‐III knockdown on IC<sub>50</sub> was assessed with small interfering RNAs.</p> </sec> <sec id="cncr28017-sec-0003" sec-type="section"> <title>RESULTS</title> <p>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, <italic>P</italic> = .01) and cell lines (1701.0 ± 376.4 versus 645.1 ± 157.9, <italic>P</italic> = .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, <italic>P</italic> = .049); p‐glycoprotein did not predict clinical outcome. USCs remained exquisitely sensitive to patupilone in vitro despite tubulin‐β‐III overexpression (IC<sub>50, USC</sub> 0.245 ± 0.11 nM versus IC<sub>50, OSC</sub> 1.01 ± 0.13 nM, <italic>P</italic> = .006).</p> </sec> <sec id="cncr28017-sec-0004" sec-type="section"> <title>CONCLUSIONS</title> <p>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. <bold><italic>Cancer</italic> 2013;119:2582–2592</bold>. © <italic>2013 American Cancer Society</italic>.</p> </sec> </abstract>