Abstract 5472: Class III beta-tubulin in castration resistant human prostate cancer

Abstract

Abstract BACKGROUND: Class III β-tubulin (βIII-tubulin) is expressed in tissues of neuronal lineage but it is also expressed in several human malignancies including non small cell lung carcinoma, breast and ovarian cancer. Overexpression of βIII-tubulin in these tumors is associated with an unfavorable outcome and resistance to taxane-based therapies. βIII-tubulin deregulation however is still poorly documented in prostate cancer. Previously, we reported that βIII-tubulin expression is increased in prostate cancer (PCa) cells by androgen ablation. Here we sought to better characterize the contribution of βIII-tubulin to castration resistant PCa, the stage of the tumor most responsible for mortality from PCa. METHODS: βIII-tubulin expression was assayed by immunohistochemistry in prostate tumors obtained from patients with castration resistant PCa. Protein expression was scored as null (0), weak (1), moderate (2) and strong (3) and considered significant when the score was 2 or more in more than 10% of cancer cells. Consecutive sections were also immunostained for neuroendocrine biomarkers, neuron specific enolase (NSE) and chromogranin A (CgA). An androgen independent (AI) variant of LNCaP cells (AI-LNCaP) was assessed for the effects of docetaxel treatment on βIII-tubulin expression. Finally, DU145 cells stably overexpressing βIII-tubulin were tested for their sensitivity to docetaxel relative to control vector-transfected cells. RESULTS: 24/40 specimens of castration resistant tumors were found to express significant levels of βIII-tubulin. In 6 out of 22 cases analyzed, regions of the tumor positively co-stained for both βIII tubulin and NSE, however none of 8 evaluated cases showed co-staining for βIII-tubulin and CgA. AI-LNCaP cells treated with 5 to 10 nM docetaxel showed a time dependent increase in βIII-tubulin expression. DU145 cells stably overexpressing βIII-tubulin were found to be more resistant to docetaxel than the parental counterpart with a 2-fold increase in the IC50. CONCLUSION: Our data indicate that βIII-tubulin is expressed in the majority of castration resistant prostate tumors. Although βIII-tubulin immunostaining of prostate tumor cells sometimes coincides with staining for neuroendocrine markers, most βIII-tubulin positive tumor cells examined did not show coincidental staining so increased βIII-tubulin expression may occur independently of NE differentiation. Regardless, our in vitro studies support a role for βIII-tubulin in the emergence of doxetaxel resistance by androgen independent human PCa cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5472.