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MDM2 Expression in Serous and Mucinous Epithelial Tumours of the Ovary

  • Abdelaal, Shereen E (Pathology Department, National Research Centre) ;
  • Habib, Fahima M (Pathology Department, Faculty of Medicine, Cairo University) ;
  • el Din, Amina A Gamal (Pathology Department, National Research Centre) ;
  • Gabal, Samia M (Pathology Department, Faculty of Medicine, Cairo University) ;
  • Hassan, Nabila S (Pathology Department, National Research Centre) ;
  • Ibrahim, Nihad A (Department of Community Medicine, National Research Centre)
  • Published : 2016.07.01

Abstract

Background: Different types of cancer exhibit abnormalities in cell cycle regulators. The murine double minute-2(MDM2) cell cycle regulator is a proto-oncogene that negatively regulates the P53 tumour suppressor gene. Surface epithelial tumours constitute approximately two thirds of ovarian neoplasms. Each histologic type can be classified as benign, borderline and malignant. This study aimed to examine immunohistochemical expression of the MDM2 protein in ovarian serous and mucinous epithelial tumours (benign, borderline and malignant). Materials and Methods: This study included forty five ovarian tumours, subdivided into fifteen cystadenomas (5 serous and 10 mucinous), fifteen borderline tumours (11 serous and 4 mucinous) and fifteen cystadenocarcinomas (9 serous and 6 mucinous). Paraffin sections were stained with haematoxylin and eosin for histopathologic study, and with mouse monoclonal anti-MDM2 antibody for immunohistochemistry. Results: MDM2 positivity was detected in 28.9% of the studied ovarian tumours. All benign tumours were negative and positivity was significantly higher in malignant than borderline tumours (P value of chi-square test =0.000). Significantly, all MDM2 positive mucinous tumours were malignant with no positive mucinous borderline tumours. Malignant tumours showed positive MDM2 expression in 83.3% of mucinous type and in 55.6% of serous type. Borderline serous tumours showed negative MDM2 in 72.7% of cases (P value of Z test =0.04). Conclusions: Alterations in the expression of the cell cycle regulator (MDM2) occur early in the process of tumourigenesis in serous and mucinous ovarian tumours. We suggest that MDM2 may be used in those tumours as a marker for risk stratification and identification of cases with cancer development and progression. We recommend further studies on MDM2 immunohistochemistry, in conjunction with adjuvant methods as DNA ploidy and FISH gene amplification, focusing on the mucinous tumours and differentiating between the three tumour categories, benign, borderline and malignant.

Keywords

Ovarian tumours;serous;mucinous;benign;borderline;malignant;MDM2

References

  1. Soussi T, Beroud C and Assessing T (2001). P53 status in human tumors to evaluate clinical outcome. Nature Reviews Cancer, 1, 233-44. https://doi.org/10.1038/35106009
  2. Tachibana M, Watanabe J, Matsushima J, et al (2003). Independence of the prognostic value of tumor suppressor protein expression in ovarian adenocarcinomas: a multivariate analysis of expression of p53, retinoblastoma, and related proteins. Int J Gynecological Pathol, 13, 598-606. https://doi.org/10.1046/j.1525-1438.2003.13391.x
  3. Miyamoto M, Takano M, Iwaya K, et al (2015). Hightemperature-required protein A2 as a predictive marker for response to chemotherapy and prognosis in patients with high-grade serous ovarian cancers. Br J Cancer, 112, 739-44. https://doi.org/10.1038/bjc.2015.1
  4. Mokhtar N, Gouda I, Adel I (2007). Malignant female genital system tumors. In 'Cancer Pathology Registry and Time Trend Analysis 2003-2004'. NCI, 77-9.
  5. Nag S, Zhang X, Srivenugopal K, et al (2014). Targeting MDM2-p53 interaction for cancer therapy: are we there yet? Curr Med Chem, 21, 553-74. https://doi.org/10.2174/09298673113206660325
  6. Ono K, Tanaka T and Tsunoda T (2000). Identification by cDNA microarray of genes involved in ovarian carcinogenesis. Cancer Res, 60, 5007-11.
  7. Palazzo J, Monzon F and Burke M (2000). Overexpression of P21WAF1/OCIP1 and MDM2 characterize serous borderline ovarian tumors. Human Pathol, 31, 698-704. https://doi.org/10.1053/hupa.2000.7641
  8. Park E, Choi K, Yoo Y, et al (2013). Nutlin-3, a small-molecule MDM2 inhibitor, sensitizes Caki cells to TRAIL-induced apoptosis through p53-mediated PUMA upregulation and ROS-mediated DR5 upregulation. Anticancer Drugs, 24, 260-9. https://doi.org/10.1097/CAD.0b013e32835c0311
  9. Rayburn E, Zhang R and He J (2005). MDM2 and human malignancies: expression, clinical pathology, prognostic markers, and implications for chemotherapy. Current Cancer Drug Targets, 5, 27-41. https://doi.org/10.2174/1568009053332636
  10. Salim E, Morimura K, Menesi A, et al (2008). Elevated oxidative stress and DNA damage and repair levels in urinary bladder carcinomas associated with Schistosomiasis. Int J Cancer, 123, 601-8. https://doi.org/10.1002/ijc.23547
  11. Skomedal H, Kristensen G, Abeler V, et al (1997). TP53 protein accumulation and gene mutation in relation to over expression of MDM2 protein in ovarian borderline tumors and stage I carcinomas. J Pathol, 181, 158-65. https://doi.org/10.1002/(SICI)1096-9896(199702)181:2<158::AID-PATH742>3.0.CO;2-8
  12. Kanthan R, Senger J, Diudea D (2010). Malignant mixed Mullerian tumors of the uterus: histopathological evaluation of cell cycle and apoptotic regulatory proteins. World J Surg Oncol, 8, 60. https://doi.org/10.1186/1477-7819-8-60
  13. Kaspar H and Crum C (2015). The utility of immunohistochemistry in the differential diagnosis of gynecologic disorders. Arch Pathol Lab Med, 139, 39-54. https://doi.org/10.5858/arpa.2014-0057-RA
  14. Khandakar B, Mathur S, Kumar L, et al (2014). Tissue biomarkers in prognostication of serous ovarian cancer following neoadjuvant chemotherapy. Bio Med Res Int, 2014, 401245.
  15. Kobel M, Kalloger S, Lee S, et al (2013). Biomarker-based ovarian carcinoma typing: a histologic investigation in the ovarian tumor tissue analysis consortium. Cancer Epidemiol Biomarkers Prev, 22, 1677 -86. https://doi.org/10.1158/1055-9965.EPI-13-0391
  16. Lee L (2003). Ovarian tumors: an overview. Atlas Genetics and Cytogenetics Oncol Haematol, 17, 47-52
  17. Lee H, Park G, Jung J, et al (2005). Diagnostic approach using the expression profiling of the P53 tumor suppressor gene and its related proteins in ovarian epithelial tumors. Int J Gynecological Cancer, 15, 453-61. https://doi.org/10.1111/j.1525-1438.2005.15308.x
  18. Ma Y, Guan T, Yao H, et al (2013). The MDM2 309T>G polymorphism and ovarian cancer risk: a meta-analysis of 1534 cases and 2211controls. PLoS One, 8, 55019. https://doi.org/10.1371/journal.pone.0055019
  19. Manfredi J (2010). The Mdm2-p53 relationship evolves: Mdm2 swings both ways as an oncogene and a tumor suppressor. Genes Dev, 24, 1580-9. https://doi.org/10.1101/gad.1941710
  20. Mir R, Tortosa A, Martinez-Soler F, et al (2013). Mdm2 antagonists induce apoptosis and synergize with cisplatin overcoming chemoresistance in TP53 wild-type ovarian cancer cells. Int J Cancer, 132, 1525-36. https://doi.org/10.1002/ijc.27832
  21. Turbin D, Cheang M, Bajdik C, et al (2006). MDM2 protein expression is a negative prognostic marker in breast carcinoma. Modern Pathol, 19, 69-74. https://doi.org/10.1038/modpathol.3800484
  22. Uhrinova S, Uhrin D, Powers H, et al (2005). Structure of free MDM2 N-terminal domain reveals conformational adjustments that accompany p53-binding. J Molecular Biol, 350, 587-98. https://doi.org/10.1016/j.jmb.2005.05.010
  23. Wang A, Guo C, Sun Y, et al (2015). Overexpression of CUEDC2 Predicts Poor Prognosis in Ovarian Serous Carcinomas. J Cancer, 6, 542-7. https://doi.org/10.7150/jca.11420
  24. Wang X, Ongkeko W, Lau A, et al (2001). A possible role of p73 on the modulation of p53 level through MDM2. Cancer Res, 61, 1589-603.
  25. Wong K, Izaguirre D, Kwan S, et al (2013). Poor survival with wild-type TP53 ovarian cancer? Gynecol Oncol, 130, 565-9. https://doi.org/10.1016/j.ygyno.2013.06.016
  26. Zhang Q, Zeng S and Lu H (2014). Targeting p53-MDM2-MDMX loop for cancer therapy. Subcell Biochem, 85, 281-319.
  27. Tuna B, Lebe B, Sis B, et al (2004). MDM2 gene expression in adipose- tissue tumors: association with tumor progression in liposarcomas. Aegean Pathol J, 1, 11-8.
  28. Tuna B, Yorukoglu K, Tuzel E, et al (2003). Expression of p53 and mdm2 and their significance in recurrence of superficial bladder cancer. Pathology - Res Practice, 199, 323-28. https://doi.org/10.1078/0344-0338-00424
  29. Cho E, Choi Y, Chae S, et al (2006). Relationship between p53-associated proteins and estrogen receptor status in ovarian serous neoplasms. Int J Gynecologic Pathol, 16, 1000-6.
  30. Coward J, Middleton K and Murphy F (2015). New perspectives on targeted therapy in ovarian cancer. Int J Womens Health, 7, 189-203.
  31. Dogan E, Saygilia U, Tunab B, et al (2005). P53 and mdm2 as prognostic indicators in patients with epithelial ovarian cancer: A multivariate analysis. Gynecologic Oncol, 97, 46-52. https://doi.org/10.1016/j.ygyno.2004.12.053
  32. Dolfi S, Jager A, Medina D, et al (2014). Fulvestrant treatment alters MDM2 protein turnover and sensitivity of human breast carcinoma cells to chemotherapeutic drugs. Cancer Letters, 350, 52-60. https://doi.org/10.1016/j.canlet.2014.04.009
  33. Foulkes W, Stamp G, Afzal S, et al (1995). MDM2 overexpression is rare in ovarian carcinoma irrespective of TP53 mutation status. Br J Cancer, 72, 883-8. https://doi.org/10.1038/bjc.1995.428
  34. Baekelandt M, Kristensen G, Nesland J, et al (1999). Clinical significance of apoptosis-Related Factors p53, MDM2, and Bcl-2 in advanced ovarian cancer. J Clin Oncol, 17, 2061-8. https://doi.org/10.1200/JCO.1999.17.7.2061
  35. Chen S, Chen X, Xiu Y, et al (2015). Inhibition of ovarian epithelial carcinoma tumorigenesis and progression by microRNA 106b mediated through the RhoC pathway. PLoS One, 10, 125714.
  36. Gamal el Din A, Badawi M, Abdel Aal Sh, et al (2015). DNA cytometry and nuclear morphometry in ovarian benign, borderline and malignant tumors. Open Access Macedonian J Medical Sci, 3, 537-44. https://doi.org/10.3889/oamjms.2015.104
  37. Gilks B, Prat J (2009). Ovarian carcinoma pathology and genetics: recent advances. Human Pathol, 40, 1213-23. https://doi.org/10.1016/j.humpath.2009.04.017
  38. Gyorgy S, Michael J, Suher O, et al (2016). Clinical use of cancer biomarkers in epithelial ovarian cancer: updated guidelines from the european group on tumor markers. Int J Gynecological Cancer, 26, 43-51. https://doi.org/10.1097/IGC.0000000000000586
  39. Hav M, Libberecht L, Ferdnande L, et al (2011). MDM2 gene amplification and protein expression in colon carcinoma: Is targeting MDM2 a new therapeutic option? Virchows Archiv, 458, 197-203. https://doi.org/10.1007/s00428-010-1012-7
  40. Jenkins L, Durell S, Mazur S, et al (2012). P53 N-terminal phosphorylation: a defining layer of complex regulation. Carcinogenesis, 33, 1441-9. https://doi.org/10.1093/carcin/bgs145