Abstract
Background
A close correlation of the p53 protein expression to nuclear pleomorphism and proliferative activity in breast cancer has been reported. The prognostic implications of p53 protein expression, however, in relation to nuclear pleomorphism and proliferative activity in breast cancer remain controversial.
Patients and Methods
Nuclear pleomorphism and immunohistochemical reactivity for p53 protein and MIB-1 were evaluated on formalin-fixed paraffin-stored sections from 250 patients with breast cancer for whom the median follow-up duration was 6.4 years.
Results
p53 protein expression was positive in 66 (26.4%) of 250 cases. Nuclear pleomorphism was grade I or II in 169 (67.6%) cases and grade I in 81 (32.4%) cases. The MIB-1 counts were more than 10% in 102 (40.8%) cases and less than 10% in 148 (59.2%) cases. There was a close correlation between p53 protein expression and nuclear pleomorphism (p < 0.0001) and between p53 protein expression and MIB-1 counts (p < 0.0001). Univariate analyses showed the 66 cases with positive p53 protein expression to have a significantly (p = 0.0284) worse disease free survival (DFS) than the 184 cases with negative p53 protein expression. A multivariate analysis, however, on the variables including all of p53 protein expression, nuclear pleomorphism and MIB-1 counts indicated the MIB-1 counts (p = 0.0041) as well as the lymph node status to be independently significant factors for DFS, while neither p53 protein expression nor nuclear pleomorphism were independently significant factors for DFS.
Conclusion
The present study demonstrated that the p53 protein expression, nuclear pleomorphism and MIB-1 counts all demonstrated prognostic significance for breast cancer, while the most significant prognostic indicator among these three biological parameters was the MIB-1 counts.
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References
Levine AJ, Momand J, Finlay CA: The p53 tumour suppressor gene.Nature 351:453–456, 1991.
Lane DP: p53, guardian of the genome.Nature 358:15–16, 1992.
Elledge RM, Allred DC: The p53 tumor suppressor gene in breast cancer.Breast Cancer Res Treat 32:39–47, 1994.
Finlay CA, Hinds PW, Tan TH, Eliyahu D, Oren M, Levine AJ: Activating mutations for transformation by p53 produce a gene product that forms an hsc70-p53 complex with an altered half-life.Mol Cell Biol 8:531–539, 1988.
Tsutsui S, Ohno S, Murakami S, Hachitanda Y, Oda S: Prognostic value of p53 protein expression in breast cancer; An immunohistochemical analysis of frozen sections in 514 Japanese women.Breast Cancer 8:194–201, 2001.
Isola J, Visakorpi T, Holli K, Kallioniemi O: Association of overexpression of tumor suppressor protein p53 with rapid cell proliferation and poor prognosis in node-negative breast cancer patients.J Natl Cancer Inst 84:1109–1114, 1992.
Allred DC, Clark GM, Elledge R, Fuqua SAW, Brown RW, Chamness GC, Osborne CK, McGuire WL: Association of p53 protein expression with tumor cell proliferation rate and clinical outcome in node-negative breastcancer.J Natl Cancer Inst 85:200–206, 1993.
Lipponen P, Ji H, Aaltomaa S, Syrjanen S, Syrjanen K: p53 protein expression in breast cancer as related to histopathological characteristics and prognosis.Int J Cancer 55:51–56, 1993.
Friedrichs K, Gluba S, Eidtmann H, Jonat W: Overexpression of p53 and prognosis in breast cancer.Cancer 72:3641–3647, 1993.
Stenmark-Askmalm M, Stal O, Sullivan S, Ferraud L, Sun X, Carstensen J. Nordenskjold B: Cellular Accumulation of p53 protein: and independent prognostic factor in stage II breast cancer.Eur J Cancer 30A:175–180, 1994.
MacGrogan G, Bonichon F, de Mascarel I, Trojani M, Durand M, Avril A, Coindre J: Prognostic value of p53 in breast invasive ductal carcinoma: an immunohistochemical study on 942 cases.Breast Cancer Res Treat 36:71–81, 1995.
Seshadri R, Leong AS, McCaul K, Firgaira FA, Setlur V, Horsfall DJ: Relationship between p53 gene abnormalities and other tumor characteristics in breast-cancer prognosis.Int J Cancer 69:135–141, 1996.
Fresno M, Molina R, Perez del Rio MJ, Alvarez S, Diaz-Iglesias JM, Garcia I, Herrero A: p53 expression is of independent predictive value in lymph node-negative breast carcinoma.Eur J Cancer 33:1268–1274, 1997.
Davidoff AM, Herndon II JE, Glover NS, Kerns BM, Pence JC, Iglehart JD, Marks JR: Relation between p53 overexpression and established prognostic factors in breast cancer.Surgery 110:259–264, 1991.
Thor AD, Moore II DH, Edgerton SM, Kawasaki ES, Reihsaus E, Lynch HT, Marcus JN, Schwartz L, Chen L, Mayall BH, Smith HS: Accumulation of p53 tumor suppressor gene protein: An independent marker of prognosis in breast cancers.J Natl Cancer Inst 84:845–855, 1992.
Swan A, Randall B, Angus B, Wright C, Henry JA, Ostrowske J, Hennessy C, Lennard TWJ, Corbett I, Horne CHW: Retinolastoma and p53 gene expression related to relapse and survival in human breast cancer:An immunohistochemical study.J Pathol 168:23–28, 1992.
Barnes DM, Dublin EA, Fisher CJ, Levison DA, Millis RR: Immunohistochemical detection of p53 protein in mammary carcinoma: An important new independent indicator of prognosis?Hum Pathol 24:469–476, 1993.
Stenmark-Askmalm M, Stal O, Olsen K, Nordenskjold B: p53 as a prognostic factor in stage I breast cancer.Br J Cancer 72:715–719, 1995.
Silverstrini R, Daidone MG, Benini E, Faranda A, Tomasic G, Boracchi P, Salvadori B, Veronesi U: Validation of p53 accumulation as a predictor of distant metastasis at 10 years of follow-up in 1400 node-negative breast cancers.Clin Cancer Res 2:2007–2013, 1996.
Bosari S, Lee AKC, Viale G, Heatley GJ, Coggi G: Abnormal p53 immunoreactivity and prognosis in node-negative breast carcinomas with long-term follow-up.Virchows Archiv A Pathol Anat 421:291–295, 1992.
Poller DN, Hutchings CE, Galea M, Bell JA, Nicholson RA, Elston CW, Blarney RW, Ellis IO: p53 expression in human breast carcinoma: relationship to expression of epidermal growth factor receptor, cerbB-2 protein overexpression, and oestrogen receptor.Br J Cancer 66:583–588, 1992.
Jacquemier J, Moles JP, Penault-Llorca F, Adelaide J, Torrente M, Viens P, Birnbaum D, Theillet C: p53 immunohistochemical analysis in breast cancer with four monoclonal antibodies: comparison of staining and PCR-SSCP results.BrJ Cancer 69:846–852, 1994.
Cunningham JM, Ingle JN, Jung SH, Cha SS, Wold LE, Fair G, Witzig TE, Krook JE, Wieand HS, Kovach JS: p53 gene expression in node-positive breast cacner: relationship to DNA ploidy and prognosis.J Natl Cancer Inst 86:1871–1873, 1994.
Pietilainen T, Lipponen P, Aaltomaa S, Eskelinen M, Kosma V, Syrjanen K: Expression of p53 protein has no independent prognostic value in breast cancer.J Pathol 177:225–232, 1995.
Rosen PP, Lesser ML, Arroy CD, Cranor M, Borgen P, Norton L: p53 in node-negative breast carcinoma: An immunohistochemical study of epidemiologic risk factors, histologic features, and prognosis.J Clin Oncol 13:821–830, 1995.
Haerslev T, Jacobsen GK: An immunohistochemical study of p53 with correlations to histopathological parameters, c-erbB-2, proliferating cell nuclear antigen, and prognosis.Hum Pathol 26:295–301, 1995.
Fitzgibbonsss PL, Page DL, Weaver D, Thor AD, Allred C, Clark GM, Ruby SG, O’Malley F, Simpson JF, Connolly JL, Hayes DF, Edge SB, Lichter A, Schnitt SJ: Prognostic factors in breast cancer. College of American pathologists consensus statement 1999.Arch Pathol Lab Med 124:966–978, 2000.
Bloom HJG, Richardson WW: Histological grading and prognosis in breast cancer.BrJ Cancer 11:359–377, 1957.
Rank F, Dombernowsky P, Jespersen NCB, Pedersen BV, Keiding N: Histologie malignancy grading of invasive ductal breast carcinoma. A regression analysis of prognostic factors in low-risk carcinomas from a multicenter trial.Cancer 60:1599–1305, 1987.
Thor AD, Liu S, Moore IIDH, Edgerton SM: Comparison of mitotic index, in vitro bromodeoxyuridine labeling, and MIB-1 assays to quantitate proliferation in breast cancer.J Clin Oncol 17:470–477, 1999.
Cattoretti G, Rilke F, Andreola S, D’Amato L, Delia D: P53 expression in breast cancer.IntJ Cancer 41:178–183, 1988.
Hurlimann J: Prognostic value of p53 protein expression in breast carcinomas.Path Res Pract 189:996–1003 1993
Merl’o GR, Bernardi A, Diella F, Venesio T, Cappa APM, Callhan R, Liscia DS: In primary human breast carcinomas mutations in exons 5 and 6 of the p53 gene are associated with a high S-phase index.Int J Cancer 54:531–535, 1993.
Sirvent JJ, Salvado MT, Santafe M, Martinez S, Brunet J, Alvaro T, Palacios J: p53 in breast cancer. Its relation to histological grade, lymph-node status, hormone receptors, cell-proliferation faraction (ki-67) and c-erbB-2. Immunohistochemical study of 153 cases.Histol Histopathol 10:531–539, 1995.
Markis A, Allred DC, Powles TJ, Dowsett M, Fernando IN, Trott PA, Ashley SE, Ormerod MG, Titley JC, Osborne CK: Cytological evaluation of biological prognostic markers from primary breast carcinomas.Breast Cancer Res Treat 44:65–74, 1997.
Leonardi E,Cristofori A, Caffo O, Palma PD: Cytometric DNA analysis and prognostic biomarkers in breast carcinoma. Expression of P53 product in the different ploidy classes.Anal Cell Pathol 15:31–45, 1997.
Bankfalvi A, Schmitz K, Mock T, Kemper M, Cubick C, Bocker W: Relationship between AgNOR proteins, Ki-67 antigen, p53 immunophenotype and differentiation markers in archival breast carcinomas.Anal Cell Pathol 17:231–242, 1998.
Prioleau J, Schnitt SJ: p53 antigen loss in stored paraffin slides.New Engl J Med 332:1521–1522, 1995.
Bruner JM, Connelly JH, Saya H: p53 protein immuno-staining in routinely processed paraffin-embedded sections.Mod Pathol 6:189–194, 1993.
MacGrogan G, Jollet I, Huet S, Sierankowski G, Picot V, Bonichon F, Coindre JM: Comparison of quantitative and semiquantitative methods of assessing MIB-1 with the S-phase fraction in breast carcinoma.Mod Pathol 10:769–776, 1997.
Jansen RLH, Hupperets PSGJ, Arends JW, Joosten-Achjanie SR, Volovics A, Schouten HC, Hillen HFP: MIB-1 labelling index is an independent prognostic marker in primary breast cancer.BrJ Cancer 78:460–465, 1998.
Gasparini G, Boracchi P, Verderio P, Bevilacqua P: Cell kinetics in human breast cancer: Comparison between the prognostic value of the cytofluorimetric s-phase fraction and that of the antibodies to Ki-67 and PCNA antigens detected by immunocytochemistry.Int J Cancer 57:822–829, 1994.
Kesgegian AA, Cnaan A: Proliferation markers in breast carcinoma. Mitotic figure count, S-phase fraction, proliferating cell nuclear antigen, Ki-67 and MIB-1 counts.Am J Clin Pathol 104:42–49, 1995.
Clahsen PC, van de Velde CJH, Duval C, Pallud C, Mandard AM, Delobelle-Deroide A, van de Broek L, va de Vijver MJ: The utility of mitotic index, oestrogen receptor and Ki-67 measurements in the creation of novel prognostic indices for node-negative breast cancer.Eur J Surg Oncol 25:356–363, 1999.
Pierga JY, Leroyer Aa, Viehl P, Mosseri V, Chevillard S, Magdelenat H: Long term prognostic value of growth fraction determination by Ki-67 immunostaining in primary operable breast cancer.Breast Cancer Res Treat 37:57–64, 1996.
MolinoA, Micciolo R, Turazza M, Bonetti F, Piubello Q, Bonetti A, Nortilli R, Pelosi G, Cetto GL: Ki-67 immunostaining in 322 primary breast cancers: Associations with clinical and pathological variables and prognosis.IntJ Cancer 74:433–437, 1997.
Brown RW, Allred DC, Clark GM, Osborne CK, Hilsenbeck SG: Prognostic value of Ki-67 compared to S-phase fraction in axillary node-negative breast cancer.Clin Cancer Res 2:585–592, 1996.
Haghbin M, McCue PA, Mansfield CM, Komamicky LT, Benammar A, Schwartz GF: Correlation of flow cytometry to clinical factors, hormone receptors, and histopathological grade in stage I and II invasive breast carcinoma.Am J Clin Oncol 19:54–58, 1996.
Gerdes J, Lemke H, Baisch H, Wacker H, Schwab U, Stein H: Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67.J Immunol 133:1710–1715, 1984.
Cattoretti G, Becker MHG, Key G, Duchrow M, Schluter C, Galle J, Gerdes J: Monoclonal antibodies against recombinant parts of the Ki-67 antigen (MIB 1 and MIB 3) detect proliferating cells in microwave-processed formalin-fixed paraffin sections.J Pathol 168:357–363, 1992.
Michalovitz D, Halevy O, Oren M: Conditional inhibition of transformation and of cell proliferation by a temperature-sensitive mutant of p53.Cell 62:671–680, 1990.
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Tsutsui, S., Yasuda, K., Higashi, H. et al. Prognostic implication of p53 protein expression in relation to nuclear pleomorphism and the MIB-1 counts in breast cancer. Breast Cancer 11, 160–168 (2004). https://doi.org/10.1007/BF02968296
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DOI: https://doi.org/10.1007/BF02968296