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Vol. 71, No. 3, 2003
Issue release date: October 2003

Prognostic Values of p53 and HER-2/neu Coexpression in Invasive Bladder Cancer in Taiwan

Tsai Y.-S. · Tzai T.-S. · Chow N.-H. · Yang W.-H. · Tong Y.-C. · Lin J.S.N. · Chang C.-C. · Cheng H.-L. · Lin Y.-M.
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Objectives: To explore the clinical significance of p53 and HER-2/neu coexpression by immunohistochemistry in patients with invasive bladder cancer in Taiwan. Methods: Paraffin-embedded tumor blocks were obtained from 67 patients with invasive bladder cancer subjected to radical cystectomy, bilateral lymph node dissection, and urinary diversion with or without systemic chemotherapy. Two observers (N.H.C. and T.S.T.), blinded to clinical outcome, reviewed the immunohistochemical staining for p53 (PAb1801) and HER-2/neu (Ab-17). The results were analyzed for progression-free survival and patient survival. Results: Positive staining for p53 and HER-2/neu was found in 30 (44.8%) and 39 (58.2%) patients. In contrast to HER-2/neu, p53 expression was significantly associated with tumor grade and pathologic stage (p = 0.040 and 0.004, respectively), and tended to be related to the nodal status (p = 0.080). Most importantly, coexpression of p53 and HER-2/neu significantly correlated with nodal metastases (p = 0.020). Univariate and multivariate analysis revealed p53 and nodal status as two independent prognostic factors. Additionally, patients with p53 and HER-2/neu coexpression had the shortest time to relapse and overall survival, irrespective of whether adjuvant chemotherapy was given or not (p = 0.005 and 0.030). Conclusions: In invasive bladder cancer, p53 was an important prognostic factor since its expression correlated with tumor grade and stage, even nodal status, whereas HER-2/neu did not show prognostic significance. Tumors with p53 and HER-2/neu coexpression were associated with nodal metastases, probably resulting in decreased progression-free survival. Although some basic studies provide some important supports, studies including larger patient cohorts would still be required to prove the hypothesis that p53 and HER-2/neu-coexpressing tumors have a worse prognosis and are more resistant to a cisplatin-based multidrug regimen.

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  1. Messing EM, Catalona W: Urothelial tumors of the urinary tract; in Walsh PC, Retik AB, Vaughan ED, Wein AJ (eds): Campbell’s Urology, ed 3. Philadelphia, Saunders, 1998, pp 2348–2349.
  2. Crawford ED, Das S, Smith JA Jr: Preoperative radiation therapy in the treatment of bladder cancer. Urol Clin North Am 1987;14:781–787.
  3. Loehrer PJ, Einhorn LH, Elson PJ, Crawford ED, Kuebler P, Tannock I, Raghavan D, Stuart-Harris R, Sarosdy MF, Lowe BA: A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: A cooperative group study. J Clin Oncol 1992;10:1066–1073.
  4. Sternberg CN, Yagoda A, Scher HI, Watson RC, Geller N, Herr HW, Morse MJ, Sogani PC, Vaughan ED, Bander N: Methotrexate, vinblastine, doxorubicin, and cisplatin for advanced transitional cell carcinoma of the urothelium: Efficacy and patterns of response and relapse. Cancer 1989;64:2448–2458.
  5. Esrig D, Elmajian D, Groshen S, Freeman JA, Stein JP, Chen SC, Nichols PW, Skinner DG, Jones PA, Cote RJ: Accumulation of nuclear p53 and tumor progression in bladder cancer. N Engl J Med 1994;331:1259–1264.
  6. Cote RJ, Esrig D, Groshen S, Jones PA, Skinner DG: p53 and treatment of bladder cancer. Nature 1997;385:123–125.
  7. Keegan PE, Lunec J, Neal DE: p53 and p53-regulated genes in bladder cancer. Br J Urol 1998;82:710–720.
  8. Moriyama M, Akiyama T, Yamamoto T, Kawamoto T, Kato T, Sato K, Watanuki T, Hikage T, Katsuta N, Mori S: Expression of c-erb B-2 gene product in urinary bladder cancer. J Urol 1991;145:423–427.
  9. Lipponen PK: Expression of c-erb B-2 oncoprotein in transitional cell bladder cancer. Eur J Cancer 1993;29A:749–753.
  10. Lee SE, Chow NH, Chi YC, Tzai TS, Yang WH, Lin SN: Expression of c-erbB-2 protein in normal and neoplastic urothelium: Lack of adverse prognostic effect in human urinary bladder cancer. Anticancer Res 1994;114:1317–1324.
  11. Miyamoto H, Kubota Y, Noguchi S, Takase K, Matsuzaki J, Moriyama M, Takebayashi S, Kitamura H, Hosaka M: c-erb B-2 gene amplification as a prognostic marker in human bladder cancer. Urology 2000;55:679–683.
  12. Olayioye MA, Neve RM, Lane HA, Hynes NE: The ErbB signaling network: Receptor heterodimerization in development and cancer. EMBO J 2000;19:3159–3167.
  13. Prenzel N, Fischer OM, Streit S, Hart S, Ullrich A: The epidermal growth factor receptor family as a central element for cellular signal transduction and diversification. Endocr Relat Cancer 2001;8:11–31.
  14. Lu Z, Jiang G, Blume-Jensen P, Hunter T: Epidermal growth factor-induced tumor cell invasion and metastasis initiated by dephosphorylation and downregulation of focal adhesion kinase. Mol Cell Biol 2001;21:4016–4031.
  15. Bullock AN, Fersht AR: Rescuing the function of mutant p53. Nat Rev Cancer 2001;1:68–76.
  16. Zhou BP, Liao Y, Xia Y, Zou Y, Spohn B, Hung MC: HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation. Nat Cell Biol 2001;3:973–982.
  17. Huang GC, Hobbs S, Walton M, Epstein RJ: Dominant negative knockout of p53 abolishes ErbB2-dependent apoptosis and permits growth acceleration in human breast cancer cells. Br J Cancer 2002;86:1104–1109.
  18. Chang FL, Lai MD: The relationship between p53 status and anticancer drugs-induced apoptosis in nine human bladder cancer cell lines. Anticancer Res 2000;20:351–356.
  19. Su SJ, Lai MD, Yeh TM, Chow NH: Overexpression of HER-2/neu enhances the sensitivity of human bladder cancer cells to urinary isoflavones. Eur J Cancer 2001;27:1413–1418.
  20. Chen C, Chauang YC, Lin TM, Wu HY: Malignant neoplasms among residents of a blackfoot disease-endemic area in Taiwan: High-arsenic artesian well water and cancers. Cancer Res 1985;45:5895–5899.
  21. Zhao CQ, Young MR, Diwan BA, Coogan TP: Association of arsenic-induced malignant transformation with DNA hypomethylation and aberrant gene expression. Proc Natl Acad Sci USA 1997;94:10907–10912.
  22. Tzai TS, Chow NH, Lin JSN, Yang WH, Tong YC: The expression of p53 and Bcl-2 in superficial bladder transitional cell carcinoma and its role in the outcome of postoperative intravesical chemotherapy. Anticancer Res 1998;18:4717–4722.
  23. Kraggerud SM, Jacobsen KD, Berner A, Stokke T, Holm R, Smedshammer L, Borresen-Dale AL, Fossa SD: A comparison of different modes for detection of p53 protein accumulation. Pathol Res Pract 1997;193:471–478.
  24. Clausen OP, Lothe RA, Borresen-Dale AL, De Angelis P, Chen Y, Rognum TO, Meling GI: Association of p53 accumulation with TP53 mutations, loss of heterozygosity at 17p13, and DNA ploidy status in 273 colorectal carcinomas. Diagn Mol Pathol 1998;7:215–223.
  25. Chow NH, Chan SH, Tzai TS, Ho CL, Liu HS: Expression profiles of ErbB family receptors and prognosis in primary transitional cell carcinoma of the urinary bladder. Clin Cancer Res 2001;7:1957–1962.
  26. Stein JP, Lieskovsky G, Cote R, Groshen S, Feng AC, Boyd S, Skinner E, Bochner B, Thangathurai D, Mikhail M, Raghavan D, Skinner DG: Radical cystectomy in the treatment of invasive bladder cancer: Long-term results in 1,054 patients. J Clin Oncol 2001;19:666–675.
  27. Lerner SP, Skinner DG, Lieskovsky G, Boyd SD, Groshen SL, Ziogas A, Skinner E, Nichols P, Hopwood B: The rationale for en bloc pelvic lymph node dissection for bladder cancer patients with nodal metastases. J Urol 1993;149:758–765.
  28. Cheng J, Huang H, Zhang ZT, Shapiro E, Pellicer A, Sun TT, Wu XR: Overexpression of epidermal growth factor receptor in urothelium elicits urothelial hyperplasia and promotes bladder tumor growth. Cancer Res 2002;62:4157–4163.
  29. Jarvinen TA, Liu ET: Effects of HER-2/neu on chemosensitivity of tumor cells. Drug Resist Updat 2000;3:319–324.
  30. Sandri MI, Isaacs RJ, Ongkeko WM, Harris AL, Hickson ID, Broggini M, Vikhanskaya F: p53 regulates the minimal promoter of the human topoisomerase IIα gene. Nucleic Acids Res 1996;24:4464–4470.
  31. Kwon Y, Shin BS, Chung IK: The p53 tumor suppressor stimulates the catalytic activity of human topoisomerase IIα by enhancing the rate of ATP hydrolysis. J Biol Chem 2000;275:18503–18510.
  32. Kielb SJ, Shah NL, Rubin MA, Sanda MG: Functional p53 mutation as a molecular determinant of paclitaxel and gemcitabine susceptibility in human bladder cancer. J Urol 2001;166:482–487.
  33. Chang FL, Lai MD: Various forms of mutant p53 confer sensitivity to cisplatin and doxorubicin in bladder cancer cells. J Urol 2001;166:304–310.
  34. Bonnefoi H, Ducraux A, Movarekhi S, Pelte MF, Bongard S, Lurati E, Iggo R: p53 as a potential predictive factor of response to chemotherapy: Feasibility of p53 assessment using a functional test in yeast from trucut biopsies in breast cancer patients. Br J Cancer 2002;86:750–755.
  35. Weller M: Predicting response to cancer chemotherapy: The role of p53. Cell Tissue Res 1998;292:435–445.
  36. Zhao CQ, Young MR, Diwan BA, Coogan TP, Waalkes MP: Association of arsenic-induced malignant transformation with DNA hypomethylation and aberrant gene expression. Proc Natl Acad Sci USA 1997;94:10907–10912.
  37. Vogt BL, Rossman TG: Effects of arsenite on p53, p21 and cyclin D expression in normal human fibroblasts – A possible mechanism for arsenite’s comutagenicity. Mutat Res 2001;478:159–168.

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