Abstract
Anti-Her-2/neu antibody is known to induce apoptosis in HER-2/neu overexpressing breast cancer cells. However, exact regulatory mechanisms mediating and controlling this phenomenon are still unknown. In the present study, we have investigated the effect of anti-Her-2/neu antibody on apoptosis of HER-2/neu overexpressing human breast cancer cell lines SK-BR-3, HTB-24, HTB-25, HTB-27, HTB-128, HTB-130 and HTB-131 in relation to p53 genotype and bcl-2 status. SK-BR-3, HTB-24, HTB-128 and HTB-130 cells exhibited mutant p53, whereas wild type p53 was found in HTB-25, HTB-27 and HTB-131 cells. All seven cell lines weakly expressed bcl-2 protein (10–20%). Anti-Her-2/neu antibody, irrespective of p53 and bcl-2 status, induced apoptosis in all 7 cell lines dose- and time-dependently and correlated with Her-2/neu overexpression. In addition, incubation of cell lines with anti-Her-2/neu antibody did not alter p53 or bcl-2 expression. Anti-HER-2/neu antibody did not induce apoptosis in HER-2/neu negative HBL-100 and HTB-132 cell lines. Our results indicate that within the panel of tested breast cancer cell lines, anti-Her-2/neu antibody-induced apoptosis was independent from the presence of intact p53. © 2001 Cancer Research Campaign http://www.bjcancer.com
Similar content being viewed by others
Article PDF
Change history
16 November 2011
This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication
References
Aas T, Borresen AL, Geisler S, Smith-Sorensen B, Johnson H, Varhaug JE, Akslen LA and Lonning PE (1996) Specific p53 mutations are associated with de novo resistance to doxorubicin in breast cancer patients. Nat Med 2: 811–814
Beham A, Marin MC, Fernandez A, Herrmann J, Brisbay S, Tari AM, Lopez-Berestein G, Lozano G, Sarkiss M and McDonnell TJ (1997) Bcl-2 inhibits p53 nuclear import following DNA damage. Oncogene 15: 2767–2772
Bergh J, Norberg T, Sjogren S, Lindgren A and Holmberg L (1995) Complete sequencing of the p53 gene provides prognostic information in breast cancer patients, particularly in relation to adjuvant systemic therapy and radiotherapy. Nat Med 1: 1029–1034
Bracey TS, Miller JC, Preece A and Paraskeva C (1995) γ-radiation-induced apoptosis in human colorectal adenoma and carcinoma cell lines can occur in the absence of wild type p53. Oncogene 10: 2391–2396
Brodowicz T, Wiltschke C, Budinsky AC, Krainer M, Steger GG and Zielinski CC (1997) Soluble HER-2/neu neutralizes biologic effects of anti-HER-2/neu antibody on breast cancer cells in vitro. Int J Cancer 73: 875–879
Brodowicz T, Wiltschke C, Kandioler-Eckersberger D, Grunt TW, Rudas M, Schneider SM, Hejna M, Budinsky A and Zielinski CC (1999) Inhibition of proliferation and induction of apoptosis in soft tissue sarcoma cells by interferon-alpha and retinoids. Br J Cancer 80: 1350–1358
Brown JM and Wouters BG (1998) Apoptosis, p53, and tumor cell sensitivity to anticancer agents. Cancer Res 59: 1391–1399
Buckbinder L, Talbott R, Velasco-Miguel S, Takenaka I, Faha B, Seizinger BR and Kley N (1995) Induction of the growth inhibitor IGF-binding protein 3 by p53. Nature 377: 646–649
Burstein HJ, Kuter I, Campos SM, Gelman RS, Tribou L, Parker LM, Manola J, Younger J, Matulonis U, Bunnell CA, Patridge AH, Richardson PG, Clarke K, Shulman LN and Winer EP (2001) Clinical activity of trastuzumab and vinorelbine in women with HER2-overexpressing metastatic breast cancer. J Clin Oncol 19: 2722–2730
Chiou SK, Rao L and White E (1994) Bcl-2 blocks p53-dependent apoptosis. Mol Cell Biol 14: 2556–2563, (abstr.)
Cobleigh MA, Vogel CL, Tripathy D, Robert NJ, Scholl S, Fehrenbacher L, Paton V, Shak S, Lieberman G and Slamon DJ (1998) Efficacy and safety of herceptin™ (humanized anti-Her2 antibody) as a single agent in 222 women with Her2 overexpression who relapsed following chemotherapy for metastatic breast cancer. Proc Am Soc Clin Oncol 17: 376a
Cobleigh MA, Vogel CL, Tripathy D, Robert NJ, Scholl S, Fehrenbacher L, Wolter JM, Paton V, Shak S, Lieberman G and Slamon DJ (1999) Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 17: 2639–2648
Coussens L, Yang-Feng TL, Liao YC, Chen E, Gray A, McGrath J, Seeburg PH, Libermann TA, Schlessinger J and Francke U (1985) Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. Science 230: 1132–1139
Delia D, Aiello A, Lombardi L, Pelicci PG, Grignani Fr, Grignani Fa, Formelli F, Menard S, Costa A, Veronesi U and Pierotti MA (1993) N-(4-hydroxyphenyl)retinamide induces apoptosis of malignant hemopoietic cell lines including those unresponsive to retinoic acid. Cancer Res 53: 6036–6041
Di Leonardo A, Linke SP, Clarkin K and Wahl GM (1994) DNA damage triggers a prolonged p53-dependent G1 arrest and long-term induction of Cipl in normal human fibroblasts. Genes Dev 8: 2540–2551
Dragovich T, Rudin CM and Thompson CB (1998) Signal transduction pathways that regulate cell survival and cell death. Oncogene 17: 3207–3213
Dyson N (1998) The regulation of E2F by pRB-family proteins. Genes Dev 12: 2245–2262
Elledge RM, Gray R, Mansour E, Yu Y, Clark GM and Ravdin P (1995) Accumulation of p53 protein as a possible predictor of response to adjuvant combination chemotherapy with cyclophosphamide, methotrexate, fluorouracil, and prednisone for breast cancer. J Natl Cancer Inst 87: 1254–1256
Fornier M, Seidman AD, Esteva FJ, Theodoulou M, Moynahan M, Currie V, Moasser M, Sklarin N, Gilewski T, Surbone A, Denton C, Bacotti D, Willey J, Bach A, Reuter V, Hortobagyi G, Norton L and Hudis C (1999) Weekly herceptin + 1 hour taxol: phase II study in Her2 overexpressing and non-overexpressing metastatic breast cancer. Proc Am Soc Clin Oncol 18: 482a (Abstr.)
Harris CC (1996) Structure and function of the p53 tumor suppressor gene: clues for rational cancer therapeutic strategies. J Natl Cancer Inst 88: 1442–1455
Harvey M, Sands AT, Weiss RS, Hegi ME, Wiseman RW, Pantazis P, Giovanella BC, Tainsky MA, Bradley A and Donehower LA (1993) In vitro growth characteristics of embryo fibroblasts isolated from p53-deficient mice. Oncogene 8: 2457–2467
Harwerth IM, Wels W, Marte BM and Hynes NE (1992) Monoclonal antibodies against the extracellular domain of the erbB-2 receptor function as partial ligand agonists. J Biol Chem 267: 15160–15167
Harwerth IM, Wels W, Schlegel J, Muller M and Hynes NE (1993) Monoclonal antibodies directed to the erbB-2 receptor inhibit in vivo tumour cell growth. Br J Cancer 68: 1140–1145
Hockenbery DM, Oltvai ZN, Yin XM, Milliman CL and Korsmeyer SJ (1993) Bcl-2 functions in an antioxidant pathway to prevent apoptosis. Cell 75: 241–251
Israeli D, Tessler E, Haupt Y, Elkeles A, Wilder S, Amson R, Telerman A and Oren M (1997) A novel p53-inducible gene, PAG608, encodes a nuclear zinc finger protein whose overexpression promotes apoptosis. EMBO J 16: 4384–4392
Johnson TM, Yu ZX, Ferrans VJ, Lowenstein RA and Finkel T (1996) Reactive oxygen species are downstream mediators of p53-dependent apoptosis. Proc Natl Acad Sci USA 93: 11848–11852
Kandioler-Eckersberger D, Ludwig C, Rudas M, Kappel S, Janschek E, Wenzel C, Schlagbauer-Wadl H, Mittlböck M, Gnant M, Steger G and Jakesz R (2000) TP53 mutation and p53 overexpression for prediction of response to neoadjuvant treatment in breast cancer patients. Clin Cancer Res 6: 50–56
Kastan MB, Onyekwere O, Sidransky D, Vogelstein B and Craig RW (1991) Participation of p53 in the cellular response to DNA damage. Cancer Res 51: 6304–6311
Kerbel RS (1999) Some recent advances in preclinical aspects of treating cancer by inhibition of tumor angiogenesis. In ASCO Educational Book, 4–7
Kerr JFR, Wyllie AH and Currie AR (1972) Apoptosis: a basic biological phenomenon with wide ranging implications in tissue kinetics. Br J Cancer 26: 239–257
Kraus MH, Popescu NC, Amsbaugh SC and King CR (1987) Overexpression of the EGF receptor-related proto-oncogene erbB-2 in human mammary tumor cell lines by different molecular mechanisms. EMBO J 6: 605–610
Kroemer G (1997) The proto-oncogene bcl-2 and its role in regulating apoptosis. Nature Med 3: 614–620
Lehman TA, Bennett WP, Metcalf RA, Welsh JA, Ecker J, Modali RV, Ullrich S, Romano JW, Appella E, Testa JR, Gerwin BI and Harris CC (1991) P53 mutations, ras mutations, and p53-heat shock 70 protein complexes in human lung carcinoma cell lines. Cancer Res 51: 4090–4096
Lupu R, Colomer R, Zugmaier G, Sarup J, Shepard M, Slamon D and Lippman ME (1990) Direct interaction of a ligand for the erbB2 oncogene product with the EGF receptor and p185erbB2. Science 249: 1552–1555
Naumovski L and Cleary ML (1996) The p53-binding protein 53BP2 also interacts with bcl2 and impedes cell cycle progression at G2/M. Mol Cell Biol 16: 3884–3892
Norton L, Slamon D, Leyland-Jones B, Wolter J, Fleming T, Eiermann W, Baselga J, Mendelsohn J, Bajamonde A, Ash M and Shak S (1999) Overall survival advantage to simultaneous chemotherapy plus the humanized anti-her2 monoclonal antibody herceptin in Her2-overexpressing metastatic breast cancer. Proc Am Soc Clin Oncol 18: 483a(abstr.)
O’Connor PM, Jackman J, Bae I, Myers TG, Fan S, Mutoh M, Scudiero DA, Monks A, Sausville EA, Weinstein JN, Friend S, Fornace AJ and Kohn KW (1997) Characterization of the p53 tumor suppressor pathway in cell lines of the National Cancer Institute anticancer drug screen and correlations with the growth-inhibitory potency of 123 anticancer agents. Cancer Res 57: 4285–4300
Owen-Schaub LB, Zhang W, Cusack JC, Angelo LS, Santee SM, Fujiwara T, Roth JA, Deisseroth AB, Zhang WW, Kruzel E and Radinsky R (1995) Wild-type human p53 and a temperature-sensitive mutant induce Fas/APO-1 expression. Mol Cell Biol 15: 3032–3040
Pegram MD, Lipton A, Hayes DF, Weber BL, Baselga JM, Tripathy D, Baly D, Baughman SA, Twaddell T, Glaspy JA and Slamon DJ (1998) Phase II study of receptor-enhanced chemosensitivity using recombinant humanized anti-p185HER2/neu monoclonal antibody plus cisplatin in patients with HER2/neu-overexpressing metastatic breast cancer refractory to chemotherapy treatment. J Clin Oncol 16: 2659–2671
Reed JC (1994) Bcl-2 and the regulation of programmed cell death. J Cell Biol 124: 1–6
Reed JC (1999) Dysregulation of apoptosis in cancer. J Clin Oncol 17: 2941–2953
Sarkis AS, Bajorin DF, Reuter VE, Herr HW, Netto G, Zhang ZF, Schultz PK, Cordon-Cardo C and Scher HI (1995) Prognostic value of p53 nuclear overexpression in patients with invasive bladder cancer treated with neoadjuvant MVAC. J Clin Oncol 13: 1384–1390
Shao ZM, Dawson MI, Li XS, Rishi AK, Sheikh MS, Han QX, Ordonez JV, Shroot B and Fontana JA (1995) p53 independent G0G1 arrest and apoptosis induced by a novel retinoid in human breast cancer cells. Oncogene 11: 493–504
Sionov RV and Haupt Y (1999) The cellular response to p53: the decision between life and death. Oncogene 18: 6145–6157
Slamon D, Leyland-Jones B, Shak S, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Baselga J and Norton L (1998) Addition of herceptin™ to first line chemotherapy for Her2 overexpressing metastatic breast cancer markedly increases anticancer activity: a randomized, multinational controlled phase III trial. Proc Am Soc Clin Oncol 17: 377a(Abstr.)
Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J and Norton L (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpress HER2. N Engl J Med 344: 783–792
Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM, Mangion J, Jacotot E, Constantini P, Loeffler M, Larochette N, Goodlett DR, Aebersold R, Siderovski DP, Penninger JM and Kroemer G (1999) Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 397: 441–446
Thompson CB (1995) Apoptosis in the pathogenesis and treatment of disease. Science 267: 1456–1462
Thor AD, Moore DH, Edgerton SM, Kawasaki ES, Reihsaus E, Lynch HT, Marcus JN, Schwartz L, Chen LC, Mayall BH and Smith HS (1992) Accumulation of p53 tumor suppressor gene protein: an independent marker of prognosis in breast cancers. J Natl Cancer Inst 84: 845–855
Venot C, Maratrat M, Dureuil C, Conseiller E, Bracco L and Debussche L (1998) The requirement for the p53 proline-rich functional domain for mediation of apoptosis is correlated with specific PIG3 gene transactivation and with transcriptional repression. EMBO J 17: 4668–4679
Wahl AF, Donaldson KL, Fairchild C, Lee FY, Foster SA, Demers GW and Galloway DA (1996) Loss of normal p53 function confers to sensitization to Taxol by increasing G2/M arrest and apoptosis. Na Med 2: 72–79
Wang XW, Vermeulen W, Coursen JD, Gibson M, Lupold SE, Forrester K, Xu G, Elmore L, Yeh H, Hoeijmakers JH and Harris CC (1996) The XPB and XPD DNA helicases are components of the p53-mediated apoptosis pathway. Genes Dev 10: 1219–1232
Wu GS, Burns TF, McDonald ER 3rd, Meng RD, Kao G, Muschel R, Yen T and EI Deiry WS (1999) Induction of the TRAIL receptor KILLER/DR5 in p53-dependent apoptosis but not growth arrest. Oncogene 18: 6411–6418
Xiong Y, Hannon GJ, Zhang H, Casso D, Kobayashi R and Beach D (1993) p21 is a universal inhibitor of cyclin kinases. Nature 366: 701–704
Yin C, Knudson CM, Korsmeyer SJ and Van Dyke T (1997) Bax suppresses tumorigenesis and stimulates apoptosis in vivo. Nature 385: 637–640
Yonish-Rouach E, Resnitzky D, Lotem J, Sachs L, Kimchi A and Oren M (1991) Wild-type p53 induces apoptosis of myeloid leukaemic cells that is inhibited by interleukin-6. Nature 352: 345–347
Zha H and Reed JC (1997) Heterodimerization-independent functions of cell death regulatory proteins bax and bcl-2 in yeast and mammalian cells. J Biol Chem 272: 31482–31488
Zhang CC, Yang JM, White E, Murphy M, Levine A and Hait WN (1998) The role of MAP4 expression in the sensitivity to paclitaxel and resistance to vinca alkaloids in p53 mutant cells. Oncogene 16: 1617–1624
Author information
Authors and Affiliations
Rights and permissions
From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
About this article
Cite this article
Brodowicz, T., Kandioler, D., Tomek, S. et al. Anti-Her-2/neu antibody induces apoptosis in Her-2/neu overexpressing breast cancer cells independently from p53 status. Br J Cancer 85, 1764–1770 (2001). https://doi.org/10.1054/bjoc.2001.2197
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1054/bjoc.2001.2197
Keywords
This article is cited by
-
Intratumoral delivery of recombinant vaccinia virus encoding for ErbB2/Neu inhibits the growth of salivary gland carcinoma cells
Journal of Translational Medicine (2014)
-
Gene expression profile and response to trastuzumab–docetaxel-based treatment in breast carcinoma
British Journal of Cancer (2009)
-
Deciphering downstream gene targets of PI3K/mTOR/p70S6K pathway in breast cancer
BMC Genomics (2008)
-
Anti-tumor immunity induced by an anti-idiotype antibody mimicking human Her-2/neu
Breast Cancer Research and Treatment (2007)
-
The efficacy of trastuzumab in Her-2/neu-overexpressing metastatic breast cancer is independent of p53 status
Journal of Cancer Research and Clinical Oncology (2005)