No conflicts of interest were declared.
Low MAD2 expression levels associate with reduced progression-free survival in patients with high-grade serous epithelial ovarian cancer†
Version of Record online: 17 JAN 2012
Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
The Journal of Pathology
Volume 226, Issue 5, pages 746–755, April 2012
How to Cite
Furlong, F., Fitzpatrick, P., O'Toole, S., Phelan, S., McGrogan, B., Maguire, A., O'Grady, A., Gallagher, M., Prencipe, M., McGoldrick, A., McGettigan, P., Brennan, D., Sheils, O., Martin, C., W Kay, E., O'Leary, J. and McCann, A. (2012), Low MAD2 expression levels associate with reduced progression-free survival in patients with high-grade serous epithelial ovarian cancer. J. Pathol., 226: 746–755. doi: 10.1002/path.3035
- Issue online: 6 MAR 2012
- Version of Record online: 17 JAN 2012
- Accepted manuscript online: 8 NOV 2011 07:30AM EST
- Manuscript Accepted: 21 OCT 2011
- Manuscript Revised: 7 OCT 2011
- Manuscript Received: 4 MAY 2011
Corrigendum: Low MAD2 expression levels associate with reduced progression-free survival in patients with high-grade serous epithelial ovarian cancer, Furlong et al., 2012, The Journal of Pathology 226; 746 – 755. DOI:10.1002/path.3035
Vol. 232, Issue 3, e1, Version of Record online: 13 JAN 2014
- epithelial ovarian cancer;
Epithelial ovarian cancer (EOC) has an innate susceptibility to become chemoresistant. Up to 30% of patients do not respond to conventional chemotherapy [paclitaxel (Taxol®) in combination with carboplatin] and, of those who have an initial response, many patients relapse. Therefore, an understanding of the molecular mechanisms that regulate cellular chemotherapeutic responses in EOC cells has the potential to impact significantly on patient outcome. The mitotic arrest deficiency protein 2 (MAD2), is a centrally important mediator of the cellular response to paclitaxel. MAD2 immunohistochemical analysis was performed on 82 high-grade serous EOC samples. A multivariate Cox regression analysis of nuclear MAD2 IHC intensity adjusting for stage, tumour grade and optimum surgical debulking revealed that low MAD2 IHC staining intensity was significantly associated with reduced progression-free survival (PFS) (p = 0.0003), with a hazard ratio of 4.689. The in vitro analyses of five ovarian cancer cell lines demonstrated that cells with low MAD2 expression were less sensitive to paclitaxel. Furthermore, paclitaxel-induced activation of the spindle assembly checkpoint (SAC) and apoptotic cell death was abrogated in cells transfected with MAD2 siRNA. In silico analysis identified a miR-433 binding domain in the MAD2 3′ UTR, which was verified in a series of experiments. Firstly, MAD2 protein expression levels were down-regulated in pre-miR-433 transfected A2780 cells. Secondly, pre-miR-433 suppressed the activity of a reporter construct containing the 3′-UTR of MAD2. Thirdly, blocking miR-433 binding to the MAD2 3′ UTR protected MAD2 from miR-433 induced protein down-regulation. Importantly, reduced MAD2 protein expression in pre-miR-433-transfected A2780 cells rendered these cells less sensitive to paclitaxel. In conclusion, loss of MAD2 protein expression results in increased resistance to paclitaxel in EOC cells. Measuring MAD2 IHC staining intensity may predict paclitaxel responses in women presenting with high-grade serous EOC. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.