Possible Usage of p63 in Bioptic Diagnostics

Czech version

Authors: Galoczová Michaela; Nenutil Rudolf; Coates Philip; Vojtěšek Bořivoj
Authors‘ workplace: Regionální centrum aplikované molekulární onkologie, Masarykův onkologický ústav, Brno
Published in: Klin Onkol 2018; 31(Supplementum 2): 27-31
Category: Reviews
doi: https://doi.org/10.14735/amko20182S27

Overview

Background:

The p63 transcription factor is a p53 homologue; however, its role in development and oncogenesis is more unambiguous than that of p53. TP63 encodes a variety of N-and C-terminal isoforms with different expression patterns and functions. The most frequently studied are N-terminal variants DNp63 (p40) and TAp63. p40 is a characteristic basal or myopithelial cell marker of stratified epithelium and it partakes in the regulation of proliferation and differentiation. The TAp63 isoform is more expressed in the suprabasal cell layer but is also expressed in primary oocytes, lymphocytes and stromal cells. It induces apoptosis and plays a role in the maintenance of genome integrity. The role of each isoform differs also in tumor progression. p40 is generally considered to behave as an oncoprotein in the regulation of cancer stem cells, while TAp63 expression is associated with a better prognosis.

Aim:

Nuclear expression of p63 is a widely used as a diagnostic marker in the clinical pathology of a spectrum of malignancies, mostly lung squamous cell carcinomas and urogenital tract carcinomas; however, it also used during examination of breast (BC) and prostate carcinoma bioptic samples. However, cytoplasmic or extracellular p63 expression is observed in neoplastic cells when the 4A4 antibody is used. This mini-review briefly summarizes the possibilities and pitfalls of p63 usage, particularly when it is used in bioptic diagnostics of BC and prostate carcinoma and highlights the potential applications of isoform specific p40 and TAp63 antibodies. It also describes other clinical usages of p63, for instance in the histogenetical classification of tumors.

Key words:

p63 – DNp63 (p40) – TAp63 – breast carcinoma – prostate carcinoma

This work was supported by the project MEYS – NPS I – LO1413.

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.

Accepted: 17. 8. 2018

Sources

1. Yang A, Kaghad M, Wang Y et al. p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities. Mol Cell 1998; 2 (3): 305–316.

2. Mangiulli M, Valletti A, Caratozzolo MF et al. Identification and functional characterization of two new transcriptional variants of the human p63 gene. Nucleic Acids Res 2009; 37 (18): 6092–6104. doi: 10.1093/nar/gkp674.

3. Kurita T, Cunha GR, Robboy SJ et al. Differential expression of p63 isoforms in female reproductive organs. Mech Dev 2005; 122 (9): 1043–1055. doi: 10.1016/j.mod.2005.04.008.

4. Chakrabarti R, Wei Y, Hwang J et al. DNp63 promotes stem cell activity in mammary gland development and basal-like breast cancer by enhancing Fzd7 expression and Wnt signalling. Nat Cell Biol 2014; 16 (10): 1004–1015, 1001–1013. doi: 10.1038/ncb3040.

5. Pignon JC, Grisanzio C, Geng Y et al. p63-expressing cells are the stem cells of developing prostate, bladder, and colorectal epithelia. Proc Natl Acad Sci U S A 2013; 110 (20): 8105–8110. doi: 10.1073/pnas.1221216110.

6. Nylander K, Vojtesek B, Nenutil R et al. Differential expression of p63 isoforms in normal tissues and neoplastic cells. J Pathol 2002; 198 (4): 417–427. doi: 10.1002/path.1231.

7. Suh EK, Yang A, Kettenbach A et al. p63 protects the female germ line during meiotic arrest. Nature 2006; 444 (7119): 624–628. doi: 10.1038/nature05337.

8. Nekulova M, Holcakova J, Nenutil R et al. Characterization of specific p63 and p63-N-terminal isoform antibodies and their application for immunohistochemistry. Virchows Arch 2013; 463 (3): 415–425. doi: 10.1007/s00428-013-1459-4.

9. Beyer U, Moll-Rocek J, Moll UM et al. Endogenous retrovirus drives hitherto unknown proapoptotic p63 isoforms in the male germ line of humans and great apes. Proc Natl Acad Sci U S A 2011; 108 (9): 3624–3629. doi: 10.1073/pnas.1016201108.

10. Guo X, Keyes WM, Papazoglu C et al. TAp63 induces senescence and suppresses tumorigenesis in vivo. Nat Cell Biol 2009; 11 (12): 1451–1457. doi: 10.1038/ncb1988.

11. Hu H, Xia SH, Li AD et al. Elevated expression of p63 protein in human esophageal squamous cell carcinomas. Int J Cancer 2002; 102 (6): 580–583. doi: 10.1002/ijc.10739.

12. Ud Din N, Qureshi A, Mansoor S. Utility of p63 immunohistochemical stain in differentiating urothelial carcinomas from adenocarcinomas of prostate. Indian J Pathol Microbiol 2011; 54 (1): 59–62. doi: 10.4103/0377-4929.77326.

13. Kamarlis RK, Lubis MN, Hernowo BS et al. Immunoexpression of P63 and SOX2 in triple-negative breast cancers, Indonesia. F1000Res 2017; 6: 1780. doi: 10.12688/f1000research.12671.2.

14. Chang K, Dai B, Kong Y et al. Basal cell carcinoma of the prostate: clinicopathologic analysis of three cases and a review of the literature. World J Surg Oncol 2013; 11 (1): 193. doi: 10.1186/1477-7819-11-193.

15. Ali TZ, Epstein JI. Basal cell carcinoma of the prostate: a clinicopathologic study of 29 cases. Am J Surg Pathol 2007; 31 (5): 697–705. doi: 10.1097/01.pas.0000213395.42075.86.

16. Nekulova M, Holcakova J, Coates P et al. The role of p63 in cancer, stem cells and cancer stem cells. Cell Mol Biol Lett 2011; 16 (2): 296–327. doi: 10.2478/s11658-011-0009-9.

17. Alexandrova EM, Moll UM. Role of p53 family members p73 and p63 in human hematological malignancies. Leuk Lymphoma 2012; 53 (11): 2116–2129. doi: 10.3109/10428194.2012.684348.

18. Boldrup L, Coates PJ, Gu X et al. DeltaNp63 isoforms differentially regulate gene expression in squamous cell carcinoma: identification of Cox-2 as a novel p63 target. J Pathol 2009; 218 (4): 428–436. doi: 10.1002/path.2560.

19. Li N, Li H, Cherukuri P et al. TA-p63-gamma regulates expression of DeltaN-p63 in a manner that is sensitive to p53. Oncogene 2006; 25 (16): 2349–2359. doi: 10.1038/sj.onc.1209270.

20. Wang X, Mori I, Tang W et al. p63 expression in normal, hyperplastic and malignant breast tissues. Breast Cancer 2002; 9 (3): 216–219.

21. Werling RW, Hwang H, Yaziji H et al. Immunohistochemical distinction of invasive from noninvasive breast lesions: a comparative study of p63 versus calponin and smooth muscle myosin heavy chain. Am J Surg Pathol 2003; 27 (1): 82–90.

22. Hill CB, Yeh IT. Myoepithelial cell staining patterns of papillary breast lesions: from intraductal papillomas to invasive papillary carcinomas. Am J Clin Pathol 2005; 123 (1): 36–44.

23. Wang Y, Jindal S, Martel M et al. Myoepithelial cells in lobular carcinoma in situ: distribution and immunophenotype. Hum Pathol 2016; 55: 126–134. doi: 10.1016/j.humpath.2016.05.003.

24. Rohilla M, Bal A, Singh G et al. Phenotypic and functional characterization of ductal carcinoma in situ-associated myoepithelial cells. Clin Breast Cancer 2015; 15 (5): 335–342. doi: 10.1016/j.clbc.2015.01.004.

25. med.stanford.edu. [online]. Ductal carcinoma in situ of the breast. Available from: http: //surgpathcriteria.stanford.edu/breast/dcis/differentialdiagnosis.html.

26. Reisenbichler ES, Ross JR, Hameed O. The clinical use of a P63/cytokeratin7/18/cytokeratin5/14 antibody cocktail in diagnostic breast pathology. Ann Diagn Pathol 2014; 18 (6): 313–318. doi: 10.1016/j.anndiagpath.2014.08.007.

27. Pavlakis K, Zoubouli C, Liakakos T et al. Myoepithelial cell cocktail (p63+SMA) for the evaluation of sclerosing breast lesions. Breast 2006; 15 (6): 705–712. doi: 10.1016/j.breast.2005.11.005.

28. Liao KC, Lee WY, Chen MJ. Myoepithelial carcinoma: a rare neoplasm of the breast. Breast Care (Basel) 2010; 5 (4): 246–249. doi: 10.1159/000313982.

29. Mastropasqua MG, Maiorano E, Pruneri G et al. Immunoreactivity for c-kit and p63 as an adjunct in the diagnosis of adenoid cystic carcinoma of the breast. Mod Pathol 2005; 18 (10): 1277–1282. doi: 10.1038/modpathol.3800423.

30. Hsiao YH, Su YA, Tsai HD et al. Increased invasiveness and aggressiveness in breast epithelia with cytoplasmic p63 expression. Int J Biol Sci 2010; 6 (5): 428–442.

31. Choi J, Kim D, Koo JS. Secretory carcinoma of breast demonstrates nuclear or cytoplasmic expression in p63 immunohistochemistry. Int J Surg Pathol 2012; 20 (4): 367–372. doi: 10.1177/1066896912440506.

32. Xu Z, Wang W, Deng CX et al. Aberrant p63 and WT-1 expression in myoepithelial cells of pregnancy-associated breast cancer: implications for tumor aggressiveness and invasiveness. Int J Biol Sci 2009; 5 (1): 82–96.

33. Alomari AK, Glusac EJ, McNiff JM. p40 is a more specific marker than p63 for cutaneous poorly differentiated squamous cell carcinoma. J Cutan Pathol 2014; 41 (11): 839–845. doi: 10.1111/cup.12388.

34. Lehmann BD, Pietenpol JA. Identification and use of biomarkers in treatment strategies for triple-negative breast cancer subtypes. J Pathol 2014; 232 (2): 142–150. doi: 10.1002/path.4280.

35. Hanker L, Karn T, Ruckhaeberle E et al. Clinical relevance of the putative stem cell marker p63 in breast cancer. Breast Cancer Res Treat 2010; 122 (3): 765–775. doi: 10.1007/s10549-009-0608-6.

36. Matos I, Dufloth R, Alvarenga M et al. p63, cytokeratin 5, and P-cadherin: three molecular markers to distinguish basal phenotype in breast carcinomas. Virchows Arch 2005; 447 (4): 688–694. doi: 10.1007/s00428-005-0010-7.

37. Koker MM, Kleer CG. p63 expression in breast cancer: a highly sensitive and specific marker of metaplastic carcinoma. Am J Surg Pathol 2004; 28 (11): 1506–1512.

38. Matkovic B, Juretic A, Separovic V et al. Immunohistochemical analysis of ER, PR, HER-2, CK 5/6, p63 and EGFR antigen expression in medullary breast cancer. Tumori 2008; 94 (6): 838–844. doi: 10.1089/jpm.2016.0362.

39. Cimino-Mathews A, Sharma R, Illei PB et al. A subset of malignant phyllodes tumors express p63 and p40: a diagnostic pitfall in breast core needle biopsies. Am J Surg Pathol 2014; 38 (12): 1689–1696. doi: 10.1097/PAS.0000000000000301.

40. Yamaguchi R, Tanaka M, Kondo K et al. Characteristic morphology of invasive micropapillary carcinoma of the breast: an immunohistochemical analysis. Jpn J Clin Oncol 2010; 40 (8): 781–787. doi: 10.1093/jjco/hyq056.

41. Bratthauer GL, Saenger JS, Strauss BL. Antibodies targeting p63 react specifically in the cytoplasm of breast epithelial cells exhibiting secretory differentiation. Histopathology 2005; 47 (6): 611–616. doi: 10.1111/j.1365-2559.2005.02282.x.

42. Kim SK, Jung WH, Koo JS. p40 (DNp63) expression in breast disease and its correlation with p63 immunohistochemistry. Int J Clin Exp Pathol 2014; 7 (3): 1032–1041.

43. Aghazadeh S, Yazdanparast R. Activation of STAT3/HIF-1a/Hes-1 axis promotes trastuzumab resistance in HER2-overexpressing breast cancer cells via down-regulation of PTEN. Biochim Biophys Acta 2017; 1861 (8): 1970–1980. doi: 10.1016/j.bbagen.2017.05.009.

44. Sailer V, Lüders C, Kuhn W et al. Immunostaining of ∆Np63 (using the p40 antibody) is equal to that of p63 and CK5/6 in high-grade ductal carcinoma in situ of the breast. Virchows Arch 2015; 467 (1): 67–70. doi: 10.1007/s00428-015-1766-z.

45. Coates PJ, Nenutil R, Holcakova J et al. p63 isoforms in triple-negative breast cancer: DNp63 associates with the basal phenotype whereas TAp63 associates with androgen receptor, lack of BRCA mutation, PTEN and improved survival. Virchows Arch 2018; 472 (3): 351–359. doi: 10.1007/s00428-018-2324-2.

46. Signoretti S, Pires MM, Lindauer M et al. p63 regulates commitment to the prostate cell lineage. Proc Natl Acad Sci U S A 2005; 102 (32): 11355–11360. doi: 10.1073/pnas.0500165102.

47. Signoretti S, Waltregny D, Dilks J et al. p63 is a prostate basal cell marker and is required for prostate development. Am J Pathol 2000; 157 (6): 1769–1775. doi: 10.1016/S0002-9440 (10) 64814-6.

48. Parsons JK, Gage WR, Nelson WG et al. p63 protein expression is rare in prostate adenocarcinoma: implications for cancer diagnosis and carcinogenesis. Urology 2001; 58 (4): 619–624.

49. Humphrey PA. Diagnosis of adenocarcinoma in prostate needle biopsy tissue. J Clin Pathol 2007; 60 (1): 35–42. doi: 10.1136/jcp.2005.036442.

50. Tan HL, Haffner MC, Esopi DM et al. Prostate adenocarcinomas aberrantly expressing p63 are molecularly distinct from usual-type prostatic adenocarcinomas. Mod Pathol 2015; 28 (3): 446–456. doi: 10.1038/modpathol.2014.115.

51. Osunkoya AO, Hansel DE, Sun X et al. Aberrant diffuse expression of p63 in adenocarcinoma of the prostate on needle biopsy and radical prostatectomy: report of 21 cases. Am J Surg Pathol 2008; 32 (3): 461–467. doi: 10.1097/PAS.0b013e318157020e.

52. Dhillon PK, Barry M, Stampfer MJ et al. Aberrant cytoplasmic expression of p63 and prostate cancer mortality. Cancer Epidemiol Biomarkers Prev 2009; 18 (2): 595–600. doi: 10.1158/1055-9965.EPI-08-0785.

53. Rekhtman N, Ang DC, Sima CS et al. Immunohistochemical algorithm for differentiation of lung adenocarcinoma and squamous cell carcinoma based on large series of whole-tissue sections with validation in small specimens. Mod Pathol 2011; 24 (10): 1348–1359. doi: 10.1038/modpathol.2011.92.

54. Bishop JA, Teruya-Feldstein J, Westra WH et al. p40 (DNp63) is superior to p63 for the diagnosis of pulmonary squamous cell carcinoma. Mod Pathol 2012; 25 (3): 405–415. doi: 10.1038/modpathol.2011.173.

55. Houghton O, McCluggage WG. The expression and diagnostic utility of p63 in the female genital tract. Adv Anat Pathol 2009; 16 (5): 316–321. doi: 10.1097/PAP. 0b013e3181b507c6.

56. Sams RN, Gnepp DR. P63 expression can be used in differential diagnosis of salivary gland acinic cell and mucoepidermoid carcinomas. Head Neck Pathol 2013; 7 (1): 64–68. doi: 10.1007/s12105-012-0403-2.

57. Zhang HJ, Xue WC, Siu MK et al. P63 expression in gestational trophoblastic disease: correlation with proliferation and apoptotic dynamics. Int J Gynecol Pathol 2009; 28 (2): 172–178. doi: 10.1097/PGP.0b013e3181895 55b.