Role of p63 in Breast Carcinoma
A Review
DOI:
https://doi.org/10.21276/apalm.1954Keywords:
p63, breast, carcinoma, diagnostic, metaplasticAbstract
p63, a recently identified member of the p53 gene family, is located on chromosome 3 q27. It has recently been proven that p63 plays an important role in the progression of ductal carcinoma in situ to infiltrating ductal carcinoma.p63 had two isoforms-one of which TA p63 which induces apoptosis and the other Np63 enhances cell proliferation and inhibits apoptosis. Also, matrix metalloproteinase, which contributes to the invasive capacity of cancer cells is a direct transcriptional target of p63. Much research is required to elucidate the functions of isoforms of p63.
p63 has diagnostic utility in breast carcinomas.p63 is documented to be specific for metaplastic carcinomas with spindle and /or squamous areas.p63is also a part of the trichromogen cocktail stain commonly used to solve diagnostic dilemmas in breast pathology. This nuclear marker with strong and diffuse staining pattern on immunohistochemistry is easily detectable, hence should be used in the diagnostic workup of challenging spindle cell tumors of the breast.
Thus in this article, the various functions and uses of p63 in breast carcinoma have been brought out. The diagnostic potential of p63 in other tumors and sarcomas still needs to be researched.
References
1) Parkin D M, Bray F, Fenay J et al. Estimating the world cancer burden:Globocan. Int J Cancer 2000; 94:153-56.
2) Parkin J M. Whelan SL, Ferlay J. Cancer incidence in five continents, vol.VII (IARCScientific Publication N143). International Agency for Research on Cancer. Lyon, France.
3) Mattia Barbareschi, Lorenza Pecciarini, M. Giulia Cangi, Ettore Macrì, Aroldo Rizzo Giuseppe Vial, Claudio Doglioni. p63, a p53 Homologue, is a Selective Nuclear Marker of Myoepithelial Cells of the Human Breast. The American Journal of Surgical Pathology 2001; 25(8): 1054–60.
4) Ahmed A. The myoepithelium in human breast carcinoma. J Pathol 1974; 113:129–35
5) Lazard D, Sastre X, Frid MG, et al. Expression of smooth muscle specific proteins in myoepithelium and stromal myofibroblasts of normal and malignant human breast tissue. Proc Natl AcadSci USA 1993; 90:999–1003.
6) Foschini MP, Scarpellini F, Gown AM, et al. Differential expression of myoepithelial markers in salivary, sweat and mammaryglands. Int J SurgPathol 2000; 8:293–7.
7) Kaelin WGJ. The emerging p53 gene family. J Natl Cancer Inst 1999; 91:594–8.
8) 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 Biol 1998; 2: 305–16.
9) Kaufmann O, Fietze E, Mengs J, et al. Value of p63 and cytokeratin 5/6 as immunohistochemical markers for the differential diagnosis of poorly differentiated and undifferentiated carcinomas. Am J ClinPathol 2001; 116:823–30.
10) Gobbi H, Olson SJ, Simpson JF, et al. Spindle cell metaplastic tumors of the breast (SCMTB) co-express p63, a novel myoepithelial marker, and epithelial markers. Mod Pathol. 2004;17(1):31A.0
11) Reis-Filho JS, Milanezi F, Paredes J, et al. Novel and classic myoepithelial/
stem cell markers in metaplastic carcinomas of the breast. Immunohistochem Mol Morphol. 2003; 11:1
12) Meryem M. Koker, and Celina G. Kleer, p63 Expression in Breast Cancer A Highly Sensitive and Specific Marker of Metaplastic Carcinoma. Am J SurgPathol Nov 2004; 28:112-15.
13) Lane DP. Cancer p53, guardian of the genome. Nature. 1992; 358:15–16.
14) Flores ER, et al. Tumor predisposition in mice mutant for p63 and p73: evidence for broader tumor suppressor functions for the p53 family. Cancer Cell 2005; 7:363–73.
15) Su X, et al. TAp63 suppresses metastasis through coordinate regulation of Dicer and miRNAs. Nature 2010; 467:986–990
16) Xiaohua Su, DeepavaliChakravarti, p63 steps into the limelight: crucial roles in the suppression of tumorigenesis and metastasis. Nat Rev Cancer. Feb 2013; 13(2): 136–143
17) Cowell CF, Weigelt B, Sakr RA, Ng CK, Hicks J, King TA et al. Progression from ductal carcinoma in situ to invasive breast cancer: revisited. MolOncol 2013; 7:859–69.
18) Ma XJ, Salunga R, Tuggle JT, Gaudet J, Enright E, McQuaryP,Payette T, Pistone M, Stecker K, Zhang BM, Zhou YX, Varnholt H, Smith B, Gadd M, Chatfield E, Kessler J, Baer TM, Erlander MG, Sgroi DC. Gene expression profiles of human breast cancer progression. Proc Natl AcadSci U S A .2003;100:5974- 79
19) Polyak K, Hu M.Do myoepithelial cells hold the key for breast tumor progression? J Mammary Gland Biol. Neoplasia 2005; 10:231-47
20) Tanya D. Russell, Sonali Jindal, SamiatAgunbiade, Dexiang Gao, Megan Troxell, Virginia F. Borges, PepperSchedin. Myoepithelial Cell Differentiation Markers in Ductal Carcinoma in Situ Progression. Am J Pathol 2015; 185: 3076-89
21) Rohilla M, Bal A, Singh G, Joshi K. Phenotypic and Functional Characterization of Ductal Carcinoma in Situ-Associated Myoepithelial Cells. Clin Breast Cancer. 2015 Oct; 15(5):335-42.
22) Welgus HG, Kobayashi DK and Jeffrey JJ. The collagen substrate specificity of rat uterus collagenase. J Biol Chem. 1983; 258(23):14162-14165.
23) Stickens D, Behonick DJ, Ortega N, Heyer B, Hartenstein B, Yu Y, Fosang AJ, Schorpp-Kistner M, Angel P and Werb Z. Altered endochondral bone development in matrix metalloproteinase 13-deficient mice. Development. 2004; 131(23):5883-95.
24) Mitchell PG, Magna HA, Reeves LM, Lopresti-Morrow LL, Yocum SA, Rosner PJ, Geoghegan KF and Hambor JE. Cloning, expression, and type II collagenolytic activity of matrix metalloproteinase-13 from human osteoarthritic cartilage. J Clin Invest. 1996; 97(3):761-68
25) [Radisky DC, Levy DD, Littlepage LE, Liu H, Nelson CM, Fata JE, Leake D, Godden EL, Albertson DG, Nieto MA, Werb Z and Bissell MJ. Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature. 2005; 436(7047):123-27.
26) Ivana Celardo1, Alexey Antonov1,2, Ivano Amelio1, Margherita AnnicchiaricoPetruzzelli3 and Gerry Melino. p63 transcriptionally regulates the expression of matrix metallopeptidase 13. Oncotarget 2014; 5.
27) Johansson N, Westermarck J, Leppa S, Hakkinen L,Koivisto L, Lopez-Otin C, Peltonen J, Heino J and Kahari VM. Collagenase 3 (matrix metalloproteinase 13) gene expression by HaCaT keratinocytes is enhanced by tumor necrosis factor alpha and transforming growth factor beta. Cell Growth Differ. 1997; 8(2):243-50.
28) Lodillinsky, E Infante, A Guichard, R Chaligné, L Fuhrmann, J Cyrta1, M Irondelle1, E Lagoutte, S Vacher, H Bonsang-Kitzis, M Glukhova, F Reyal, I Bièche, A Vincent-Salomon, and P Chavrier. p63/MT1-MMP axis is required for in situ to invasive transition in basal-like breast cancer.Oncogene 2016; 35: 344–57
29) Livasy CA, Karaca G, Nanda R, Tretiakova MS, Olopade OI, Moore DT, Perou CM. Phenotypic evaluation of the basal-like subtype of invasive breast carcinoma. Mod Pathol. 2006; 192: 264-71
30) Shekhar M, Kato I, Nangia-Makker P, Tait L. Comedo-DCIS is a precursor lesion for basal-like breast carcinoma: identification of a novel p63/Her2/neu expressing subgroup. Oncotarget 2013; 4(2).
31) Ginter PS, Varma S, Liu YF, Shin SJ.The minimal carcinoma triple stain is superior to commercially available multiplex immunohistochemical stains: breast triple stain and LC/DC breast cocktail.Am J ClinPathol. 2015 Dec; 144(6):869-79.
32) Yang Y, Suzuki K, Abe E, Li C, Uno M, Akiyama F, Yamauchi H, Kikuchi M, Ohde S, Deshpande G, Shibahara Y, Nakamura Y, Sasano H. The significance of combined CK5/6and p63 immunohistochemistry in predicting the risks of subsequent carcinoma development in intraductal papilloma of the breast.Pathol Int. 2015 Feb;65(2):81-8
33) Sang Kyum Kim, Woo Hee Jung, JaSeung Koo.p40 (ΔNp63) expression in breast disease and its correlation with p63 immunohistochemistry. Int J ClinExpPathol 2014;7(3):1032-1041
34) Bence KÅ‘vári , A. MarcellSzász , Janina Kulka , Zlatko MaruÅ¡ić , BozenaÅ arÄević , LászlóTiszlavicz , GáborCserni. Evaluation of p40 as a Myoepithelial Marker in Different Breast Lesions. Pathobiology 2015; 82:166–171
35) Doina Ivan, Jason W. Nash, Victor G. Prieto, Eduardo Calonje, Stephen Lyle, A. Hafeez Diwan Alexander J. F. Lazar. Use of p63 expression in distinguishing primary and metastatic cutaneous adnexal neoplasms from metastatic adenocarcinoma to skin. J Cutan Pathol 2007: 34: 474–480
36) Di Como CJ, Urist MJ, Babayan I, et al. p63 expression profiles in normal and tumor tissues. Clin Cancer Res 2002; 8: 494.
37) Reis-Filho JS, Simpson PT, Martins A, Preto A, Gartner F, Schmitt FC. Distribution of p63, cytokeratins 4/6 and cytokeratin 14 and 51 in normal and 400 neoplastic humans
tissue samples using TARP-4 multi-tumor tissue microarray.
Virchows Arch 2003; 443: 122.
2) Parkin J M. Whelan SL, Ferlay J. Cancer incidence in five continents, vol.VII (IARCScientific Publication N143). International Agency for Research on Cancer. Lyon, France.
3) Mattia Barbareschi, Lorenza Pecciarini, M. Giulia Cangi, Ettore Macrì, Aroldo Rizzo Giuseppe Vial, Claudio Doglioni. p63, a p53 Homologue, is a Selective Nuclear Marker of Myoepithelial Cells of the Human Breast. The American Journal of Surgical Pathology 2001; 25(8): 1054–60.
4) Ahmed A. The myoepithelium in human breast carcinoma. J Pathol 1974; 113:129–35
5) Lazard D, Sastre X, Frid MG, et al. Expression of smooth muscle specific proteins in myoepithelium and stromal myofibroblasts of normal and malignant human breast tissue. Proc Natl AcadSci USA 1993; 90:999–1003.
6) Foschini MP, Scarpellini F, Gown AM, et al. Differential expression of myoepithelial markers in salivary, sweat and mammaryglands. Int J SurgPathol 2000; 8:293–7.
7) Kaelin WGJ. The emerging p53 gene family. J Natl Cancer Inst 1999; 91:594–8.
8) 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 Biol 1998; 2: 305–16.
9) Kaufmann O, Fietze E, Mengs J, et al. Value of p63 and cytokeratin 5/6 as immunohistochemical markers for the differential diagnosis of poorly differentiated and undifferentiated carcinomas. Am J ClinPathol 2001; 116:823–30.
10) Gobbi H, Olson SJ, Simpson JF, et al. Spindle cell metaplastic tumors of the breast (SCMTB) co-express p63, a novel myoepithelial marker, and epithelial markers. Mod Pathol. 2004;17(1):31A.0
11) Reis-Filho JS, Milanezi F, Paredes J, et al. Novel and classic myoepithelial/
stem cell markers in metaplastic carcinomas of the breast. Immunohistochem Mol Morphol. 2003; 11:1
12) Meryem M. Koker, and Celina G. Kleer, p63 Expression in Breast Cancer A Highly Sensitive and Specific Marker of Metaplastic Carcinoma. Am J SurgPathol Nov 2004; 28:112-15.
13) Lane DP. Cancer p53, guardian of the genome. Nature. 1992; 358:15–16.
14) Flores ER, et al. Tumor predisposition in mice mutant for p63 and p73: evidence for broader tumor suppressor functions for the p53 family. Cancer Cell 2005; 7:363–73.
15) Su X, et al. TAp63 suppresses metastasis through coordinate regulation of Dicer and miRNAs. Nature 2010; 467:986–990
16) Xiaohua Su, DeepavaliChakravarti, p63 steps into the limelight: crucial roles in the suppression of tumorigenesis and metastasis. Nat Rev Cancer. Feb 2013; 13(2): 136–143
17) Cowell CF, Weigelt B, Sakr RA, Ng CK, Hicks J, King TA et al. Progression from ductal carcinoma in situ to invasive breast cancer: revisited. MolOncol 2013; 7:859–69.
18) Ma XJ, Salunga R, Tuggle JT, Gaudet J, Enright E, McQuaryP,Payette T, Pistone M, Stecker K, Zhang BM, Zhou YX, Varnholt H, Smith B, Gadd M, Chatfield E, Kessler J, Baer TM, Erlander MG, Sgroi DC. Gene expression profiles of human breast cancer progression. Proc Natl AcadSci U S A .2003;100:5974- 79
19) Polyak K, Hu M.Do myoepithelial cells hold the key for breast tumor progression? J Mammary Gland Biol. Neoplasia 2005; 10:231-47
20) Tanya D. Russell, Sonali Jindal, SamiatAgunbiade, Dexiang Gao, Megan Troxell, Virginia F. Borges, PepperSchedin. Myoepithelial Cell Differentiation Markers in Ductal Carcinoma in Situ Progression. Am J Pathol 2015; 185: 3076-89
21) Rohilla M, Bal A, Singh G, Joshi K. Phenotypic and Functional Characterization of Ductal Carcinoma in Situ-Associated Myoepithelial Cells. Clin Breast Cancer. 2015 Oct; 15(5):335-42.
22) Welgus HG, Kobayashi DK and Jeffrey JJ. The collagen substrate specificity of rat uterus collagenase. J Biol Chem. 1983; 258(23):14162-14165.
23) Stickens D, Behonick DJ, Ortega N, Heyer B, Hartenstein B, Yu Y, Fosang AJ, Schorpp-Kistner M, Angel P and Werb Z. Altered endochondral bone development in matrix metalloproteinase 13-deficient mice. Development. 2004; 131(23):5883-95.
24) Mitchell PG, Magna HA, Reeves LM, Lopresti-Morrow LL, Yocum SA, Rosner PJ, Geoghegan KF and Hambor JE. Cloning, expression, and type II collagenolytic activity of matrix metalloproteinase-13 from human osteoarthritic cartilage. J Clin Invest. 1996; 97(3):761-68
25) [Radisky DC, Levy DD, Littlepage LE, Liu H, Nelson CM, Fata JE, Leake D, Godden EL, Albertson DG, Nieto MA, Werb Z and Bissell MJ. Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature. 2005; 436(7047):123-27.
26) Ivana Celardo1, Alexey Antonov1,2, Ivano Amelio1, Margherita AnnicchiaricoPetruzzelli3 and Gerry Melino. p63 transcriptionally regulates the expression of matrix metallopeptidase 13. Oncotarget 2014; 5.
27) Johansson N, Westermarck J, Leppa S, Hakkinen L,Koivisto L, Lopez-Otin C, Peltonen J, Heino J and Kahari VM. Collagenase 3 (matrix metalloproteinase 13) gene expression by HaCaT keratinocytes is enhanced by tumor necrosis factor alpha and transforming growth factor beta. Cell Growth Differ. 1997; 8(2):243-50.
28) Lodillinsky, E Infante, A Guichard, R Chaligné, L Fuhrmann, J Cyrta1, M Irondelle1, E Lagoutte, S Vacher, H Bonsang-Kitzis, M Glukhova, F Reyal, I Bièche, A Vincent-Salomon, and P Chavrier. p63/MT1-MMP axis is required for in situ to invasive transition in basal-like breast cancer.Oncogene 2016; 35: 344–57
29) Livasy CA, Karaca G, Nanda R, Tretiakova MS, Olopade OI, Moore DT, Perou CM. Phenotypic evaluation of the basal-like subtype of invasive breast carcinoma. Mod Pathol. 2006; 192: 264-71
30) Shekhar M, Kato I, Nangia-Makker P, Tait L. Comedo-DCIS is a precursor lesion for basal-like breast carcinoma: identification of a novel p63/Her2/neu expressing subgroup. Oncotarget 2013; 4(2).
31) Ginter PS, Varma S, Liu YF, Shin SJ.The minimal carcinoma triple stain is superior to commercially available multiplex immunohistochemical stains: breast triple stain and LC/DC breast cocktail.Am J ClinPathol. 2015 Dec; 144(6):869-79.
32) Yang Y, Suzuki K, Abe E, Li C, Uno M, Akiyama F, Yamauchi H, Kikuchi M, Ohde S, Deshpande G, Shibahara Y, Nakamura Y, Sasano H. The significance of combined CK5/6and p63 immunohistochemistry in predicting the risks of subsequent carcinoma development in intraductal papilloma of the breast.Pathol Int. 2015 Feb;65(2):81-8
33) Sang Kyum Kim, Woo Hee Jung, JaSeung Koo.p40 (ΔNp63) expression in breast disease and its correlation with p63 immunohistochemistry. Int J ClinExpPathol 2014;7(3):1032-1041
34) Bence KÅ‘vári , A. MarcellSzász , Janina Kulka , Zlatko MaruÅ¡ić , BozenaÅ arÄević , LászlóTiszlavicz , GáborCserni. Evaluation of p40 as a Myoepithelial Marker in Different Breast Lesions. Pathobiology 2015; 82:166–171
35) Doina Ivan, Jason W. Nash, Victor G. Prieto, Eduardo Calonje, Stephen Lyle, A. Hafeez Diwan Alexander J. F. Lazar. Use of p63 expression in distinguishing primary and metastatic cutaneous adnexal neoplasms from metastatic adenocarcinoma to skin. J Cutan Pathol 2007: 34: 474–480
36) Di Como CJ, Urist MJ, Babayan I, et al. p63 expression profiles in normal and tumor tissues. Clin Cancer Res 2002; 8: 494.
37) Reis-Filho JS, Simpson PT, Martins A, Preto A, Gartner F, Schmitt FC. Distribution of p63, cytokeratins 4/6 and cytokeratin 14 and 51 in normal and 400 neoplastic humans
tissue samples using TARP-4 multi-tumor tissue microarray.
Virchows Arch 2003; 443: 122.
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27-09-2018
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Santara AK, Kumar A, Singh B, Doshetty R. Role of p63 in Breast Carcinoma: A Review. Ann of Pathol and Lab Med [Internet]. 2018 Sep. 27 [cited 2024 Nov. 24];5(9):R1-6. Available from: http://pacificejournals.com/journal/index.php/apalm/article/view/1954
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Copyright (c) 2018 Akriti Kashyap Santara, Ashwini Kumar, Brajesh Singh, Rohini Doshetty
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