Identification of pathogenesis pathway in basal-like breast cancer based on mutant p53 protein and topoisomerase-IIα expression
Background: Basal-like breast cancer is difficult to treat with standard regimen therapy, because it doesnât express hormone receptors or epidermal growth factor receptors. Identification of oncogenesis pathway is expected to find molecules which can be used as target for therapy. One candidate molecule is topoisomerase-IIα whose expression is regulated by p53. This study aimed to compare the expression of mutant p53 proteins and topoisomerase IIα in basal-like and non basal-like breast cancer, and to determine the association between mutant p53 proteins and topoisomerase IIα in basal-like group.
Methods: The samples were 40 formalin fixed paraffin embedded tissues from verified triple negative breast cancer tissue. The samples were divided into 2 groups, basal-like and non basal-like breast cancer, based on cytokeratin - 5 (CK-5) expression. Mutant p53 proteins and topoisomerase IIα were stained using immunohistochemistry method, scored and compared. Statistical test used SPSS software version 16 for descriptive statistics, kappa test, normality test, comparison of two mean, and categorical comparison.
Results: Median (min-max) of mutant p53 protein expression in basal-like group was 21 (0-100), the non basal-like group was 2 (0-80), p = 0.061. Min-max of topoisomerase IIα in basal-like group was 263 (15-492), non basal-like group was 262 (0-481), p = 0.409. There was an association between mutant p53 positivity with breast cancer subtype (p = 0.027) and between mutant p53-topoisomerase IIα coexpression with breast cancer subtype (p = 0.018).
Conclusion: Co-expression of mutant p53 with topoisomerase IIα has the role in one of the pathway of basal-like breast cancer pathogenesis.
World Health Organization [Internet]. Breast cancer: prevention and control. Breast cancer. [updated 2008; cited 2010 Dec 20]. Available from: http://www.who.int/cancer/detection/breastcancer/en/
Rakha E, Reis-Filho JS. Basal like breast carcinoma from expression profiling to routine practice. Arch Pathol Lab Med.2009;133(6):860-8. http://.dx.doi: 10.1200/JCO.2007.13.1748
Lester SC. The breast. In: Kumar V, Abbas AK, Fausto N, Aster JC, editors. Robbins and Cotran pathologic basis of disease. 8th ed. Philadelphia, PA: Sauders Elseviers; 2010. p. 1065-96. http://dx.doi.org/10.1016/B978-1-4377-0792-2.50028-6
Perou CM, Sørlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits of human breast tumours. Nature. 2000;406(6797):747-52. http://dx.doi.org/10.1038/35021093
Rakha E, Reis-Filho JS, Ellis IO. Basal-like breast cancer: a critical review. J Clin Oncol. 2008;26(15):2568-81. http://dx.doi.org/10.1200/JCO.2007.13.1748
Holstege H, Joosse SA, van Oostrom CT, Nederlof PM, de Vries A, Jonkers J. High Incidence of protein truncating TP53 mutations in BRCA-1 related breast cancer. Cancer Res. 2009;69(8):3625-33. http://dx.doi.org/10.1158/0008-5472.CAN-08-3426
Wang Q, Zambetti GP, Suttle DP. Inhibition of DNA topoisomerase IIα gene expression by the p53 tumor suppressor. Mol Cell Biol. 1997;17(1):389-97.
Sandri MI, Isaacs RJ, Ongkeko WM, Harris AL, Hickson ID, Broggini M, et al. p53 regulates the minimal promoter of the human topoisomerase IIα gene. Nucleic Acids Res.1996;24(22):4464-70. http://dx.doi.org/10.1093/nar/24.22.4464
Roca J. Survey and summary topoisomerase II: a fitted mechanism for the chromatin landscape. Nucleic Acid Res.2009;37(3):721-30. http://dx.doi.org/10.1093/nar/gkn994
Nitiss JL. DNA topoisomerase II and its growing repertoire of biological function. Nat Rev Cancer. 2009;9(5):327-37. http://dx.doi.org/10.1038/nrc2608
Hellemans P, van Dam PA, Geyskens M, van Oosterom AT, Buytaert P, Van Marck E. Immunohistochemical study of topoisomerase II-α ekspression in primary ductal carcinoma of the breast. J Clin Pathol.1995;48(2):147-50. http://dx.doi.org/10.1136/jcp.48.2.147
Sørlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A. 2001;98(19):10869-74. http://dx.doi.org/10.1073/pnas.191367098
Nitiss JL. Targeting DNA topoisomerase II in cancer chemotherapy. Nat Rev Cancer. 2009;9(5):338-50. http://dx.doi.org/10.1038/nrc2607
Dogu GG, Ozkan M, Ozturk F, Dikilitas M, Er O, Ozturk A. Triple-negative breast cancer: immunohistochemical correlation with basaloid markers and prognostic value of survivin. Med Oncol.2010;27(1):34-9. http://dx.doi.org/10.1007/s12032-009-9166-3
Lukas J, Niu N, Press MF. p53 mutations and expression in breast carcinoma in situ. Am J Pathol.2000;156(1):183-91. http://dx.doi.org/10.1016/S0002-9440(10)64718-9
Conforti R, Boulet T, Tomasic G, Spielmann M, Delaloge S, Arriagada R, et al. Predictive value of MRP2, p53, bcl2 and topoisomerase II immunostainings for the efficacy of anthracyclines-based adjuvant chemotherapy in breast cancer: Results from two randomized trials. J Clin Oncol (Meeting Abstracts). 2008;26(15 Suppl):616.
Turner NC, Reis-Filho JS, Russell AM, Springall RJ, Ryder K, Steele D, et al. BRCA1 dysfunction in sporadic basal-like breast cancer. Oncogene. 2007;26(14):2126-32. http://dx.doi.org/10.1038/sj.onc.1210014
Ahmed M, Lalloo F, Evans DG. Update on genetic predisposition to breast cancer. Expert Rev Anticancer Ther. 2009;9(8):1103-13. http://dx.doi.org/10.1586/era.09.38
Romero A, Martín M, Cheang MC, López García-Asenjo JA, Oliva B, He X, et al. Assessment of topoisomerase II α status in breast cancer by quantitative PCR, gene expression microarrays, immunohistochemistry, and fluorescence in situ hybridization. Am J Pathol.2011:178(4):1453-60. http://dx.doi.org/10.1016/j.ajpath.2010.12.042
Woessner RD, Mattern MR, Mirabelli CK, Jhonson RK, Drake FH. Proliferation- and cell cyle-dependent differences in expression of the 170 kilodalton and 180 kilodalton forms of topoisomerase II in NIH-3T3 cells. Cell Growth Differ.1991;2(4):209-14.
Moelans CB, de Weger RA, van Blokland MT, van der Wall E, van Diest PJ. Simultaneous detection of TOP2A and HER2 gene amplification by multiplex ligation-dependent probe amplification in breast cancer. Mod Pathol. 2010;23(1):62-70. http://dx.doi.org/10.1038/modpathol.2009.136
Vojtĕsek B, Bártek J, Midgley CA, Lane DP. An immunochemical analysis of the human nuclear phosphoprotein p53 new monoclonal antibodies and epitope mapping using recombinant p53. J Immunol Methods.1992:151(1-2):237-44. http://dx.doi.org/10.1016/0022-1759(92)90122-A
Cooper K, Haffajee Z. bcl-2 and p53 protein expression in follicular lymphoma. J Pathol. 1997;182(3):307-10. http://dx.doi.org/10.1002/(SICI)1096-9896(199707)182:3<307::AID-PATH873>3.0.CO;2-6
Sjögren S1, Inganäs M, Norberg T, Lindgren A, Nordgren H, Holmberg L, et al. The p53 gene in breast cancer: prognostic value of complementary DNA sequencing versus immunohistochemistry. J Natl Cancer Inst.1996;88(3-4):173-82. http://dx.doi.org/10.1093/jnci/88.3-4.173
Varna M, Bousquet G, Plassa LF, Bertheau P, Janin A. TP53 status and response to treatment in breast cancers. J Biomed Biotech.2011;1-9. http://dx.doi.org/10.1155/2011/284584
Copyright (c) 2015 Yayi Dwina, Ria Kodariah, Endang S.R. Hardjolukito
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Authors who publish with Medical Journal of Indonesia agree to the following terms:
- Authors retain copyright and grant Medical Journal of Indonesia right of first publication with the work simultaneously licensed under a Creative Commons Attribution-NonCommercial License that allows others to remix, adapt, build upon the work non-commercially with an acknowledgment of the work’s authorship and initial publication in Medical Journal of Indonesia.
- Authors are permitted to copy and redistribute the journal's published version of the work non-commercially (e.g., post it to an institutional repository or publish it in a book), with an acknowledgment of its initial publication in Medical Journal of Indonesia.