Class III β-tubulin expression in advanced-stage serous ovarian carcinoma effusions is associated with poor survival and primary chemoresistance.
ABSTRACT The objective of this study was to analyze the clinical role of nestin, a stem cell marker, and class III β-tubulin in advanced-stage serous ovarian carcinoma. Nestin and class III β-tubulin protein expression were investigated in 217 effusions using immunohistochemistry. Results were analyzed for association with clinicopathologic parameters including chemotherapy response and survival. Class III β-tubulin and nestin were expressed in tumor cells in 98.6% and 95.6% of specimens, respectively. Staining extent was comparable in prechemotherapy and postchemotherapy effusions. No association was found with patient age, histologic grade, International Federation of Gynecology and Obstetrics stage, primary surgery versus secondary debulking, or residual disease volume. High class III β-tubulin expression in prechemotherapy effusions was significantly associated with primary chemoresistance (progression-free survival <6 months; P = .036) and with a trend for less favorable response to first-line treatment (P = .054). In univariate survival analysis, high class III β-tubulin expression in prechemotherapy effusions was significantly associated with poor overall survival (P = .021), with a trend for poor progression-free survival (P = .067). These associations did not have independent prognostic value in Cox multivariate analysis. Nestin expression was unrelated to chemoresistance or survival. Both class III β-tubulin and nestin are frequently expressed in serous ovarian carcinoma cells in effusions. Nestin does not provide predictive or prognostic data in this patient group, whereas class III β-tubulin expression in prechemotherapy effusions is associated with poor chemoresponse and shorter survival, suggesting that it may be a therapeutic target in ovarian cancer.
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ABSTRACT: Epithelial ovarian cancer (EOC) is the most deadly tumor of the female reproductive system. Despite improvements in understanding the biology of EOC, therapeutic strategies still depend on surgery and combination of taxane and platinum agents. Here, we provide a summary of clinically tested biomarkers potentially useful to predict drug response. Resistance against platinum derivatives can result from lower drug concentrations, alterations in the target molecule and changes in the cellular signal transduction pathways. Taxane resistance can develop due to decreased intracellular drug concentration, alterations in microtubuli structure and changes in the cellular response including ERBB2 (epidermal growth factor receptor 2). A few key genes have been suggested as biomarkers for hormonal therapy. Currently, the only targeted therapy agent approved for ovarian cancer is the VEGF (vascular endothelial growth factor) inhibitor bevacizumab. Response to bevacizumab is correlated with VEGF-A levels and hypertension. The primary problems in identifying reliable biomarkers for EOC are the usage of different clinical endpoints, multivariate analysis for a panel of clinical parameters and the lack of published comprehensive clinical information of patients enrolled in these studies. The future lies in adding targeted agents to the taxane/platinum gold standard and in a more detailed stratification of patients into sub-cohorts enabling a more effective therapy. In conclusion, a large-scale coordinated effort is needed for the robust validation of the numerous biomarker candidates available in EOC therapy.Current cancer drug targets 03/2014; DOI:10.2174/1568009614666140310120107 · 3.58 Impact Factor
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ABSTRACT: Ovarian clear cell carcinomas (OCCCs) account for about 5-13% of all epithelial ovarian carcinomas in Western populations. It is characterised by resistance to conventional platinum-based chemotherapy, and new therapeutic strategies are urgently required. This article will focus on how recent discoveries have enhanced our understanding of the molecular pathogenesis of OCCCs, leading to new therapeutic opportunities. These include mutations in ARID1A, which provides a link to endometriosis, upregulation of the phosphatidylinositol 3-kinase/AKT pathway, particularly through mutations of PIK3CA and inactivation of PTEN, and increased activity of pathways involved in angiogenesis. Targeting HER2, apoptotic escape mechanisms and mismatch repair defects offer additional opportunities for treating this enigmatic tumour subtype.British Journal of Cancer advance online publication, 4 April 2013; doi:10.1038/bjc.2013.126 www.bjcancer.com.British Journal of Cancer 04/2013; 108(8). DOI:10.1038/bjc.2013.126 · 4.82 Impact Factor
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ABSTRACT: We studied mechanisms of resistance to the novel taxane cabazitaxel in established cellular models of taxane resistance. We also developed cabazitaxel-resistant variants from MCF-7 breast cancer cells by stepwise selection in drug alone (MCF-7/CTAX) or drug plus the transport inhibitor PSC-833 (MCF-7/CTAX-P). Among multidrug resistant (MDR) variants, cabazitaxel was relatively less cross-resistant than paclitaxel and docetaxel (15 vs. 200-fold in MES-SA/Dx5 and 9 vs. 60-fold in MCF-7/TxT50, respectively). MCF-7/TxTP50 cells that were negative for MDR but had 9-fold resistance to paclitaxel were also 9-fold resistant to cabazitaxel. Selection with cabazitaxel alone (MCF-7/CTAX) yielded 33-fold resistance to cabazitaxel, 52-fold resistance to paclitaxel, activation of ABCB1, and 3-fold residual resistance to cabazitaxel with MDR inhibition. The MCF-7/CTAX-P variant did not express ABCB1, nor did it efflux rhodamine-123, BODIPY-labeled paclitaxel, and [3H]-docetaxel. These cells are hypersensitive to depolymerizing agents (vinca alkaloids and colchicine), have reduced baseline levels of stabilized microtubules, and impaired tubulin polymerization in response to taxanes (cabazitaxel or docetaxel) relative to MCF-7 parental cells. Class III beta-tubulin (TUBB3) RNA and protein were elevated in both MCF-7/CTAX and MCF-7/CTAX-P. Decreased BRCA1 and altered epithelial-mesenchymal transition (EMT) markers are also associated with cabazitaxel resistance in these MCF-7 variants, and may serve as predictive biomarkers for its activity in the clinical setting. In summary, cabazitaxel resistance mechanisms include MDR (although at a lower level than paclitaxel and docetaxel), and alterations in microtubule dynamicity, as manifested by higher expression of TUBB3, decreased BRCA1, and by the induction of EMT. Copyright © 2014, American Association for Cancer Research.Molecular Cancer Therapeutics 11/2014; 14(1). DOI:10.1158/1535-7163.MCT-14-0155 · 6.11 Impact Factor