Abstract
Anti-oestrogen is effective for the treatment of oestrogen receptor (ER)-positive breast carcinomas, butmost of these tumours become resistant to anti-oestrogen. It has been suggested that anti-oestrogen therapy may induce a HER2signalling pathway in breast cancer cells and this may cause resistance to anti-oestrogen. Thus, it is conceivable that combinedtherapy with anti-oestrogen and anti-HER2 antibody might be more effective. In the present study, we investigated the effect ofcombined treatment with a humanized anti-HER2 monoclonal antibody, rhumAbHER2 (trastuzumab), and an anti-oestrogen, ICI 182,780, onthe cell growth of three human breast cancer cell lines which respectively express different levels of ER and HER2. The combinedtreatment enhanced the growth inhibitory effect on ML-20 cells, which express a high level of ER and a moderate level of HER2, butshowed no additive effect on either KPL-4 cells, which express no ER and a moderate level of HER2, or MDA-MB-231 cells, which express no ER and a low level of HER2. It is also suggested that both the antibody and anti-oestrogen induce a G1–S blockade and apoptosis. These findings indicate that combined treatment with anti-HER2 antibody and anti-oestrogen may be useful for thetreatment of patients with breast cancer expressing both ER and HER2. © 2000 Cancer Research Campaign
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
Baselga J, Tripathy D, Mendelsohn J, Baughman S, Benz CC, Dantis L, Skalarin NT, Seidman AD, Hudis CA, Moore J, Rosen PP, Twaddell T, Henderson IC and Norton L (1996) Phase II study of weekly intravenous recombinant humanized anti-p185HER2monoclonal antibody in patients with HER2/ neu -overexpressing metastatic breast cancer. J Clin Oncol 14: 737–744
Baselga J, Norton L, Albanell J, Kim YM and Mendelsohn J (1998) Recombinant humanized anti-HER2 antibody (Herceptin) enhances the antitumor activity of paclitaxel and doxorubicin against HER2/neu overexpressing human breast cancer xenografts. Cancer Res 58: 2825–2831
Benz CC, Scott GK, Sarup JC, Johnson RM, Tripathy D, Coronado E, Shepard HM and Osborne CK (1992) Estrogen-dependent, tamoxifen-resistant tumorigenic growth of MCF-7 cells transfected with HER2/neu. Breast Cancer Res Treat 24: 85–95
Bianco AR, Laurentis MDe, Carlomgno C, Lauria R, Petrella G, Pianco L, Pettinato G, Perrone F, Gallo C, Marinelli A and De Placido S (1998) Twenty-year update the Naples gun trial of adjuvant breast cancer therapy: evidence of interaction between c-erbB2 expression and tamoxifen efficacy. Proc ASCO 17: 97
Carter P, Presta L, Gorman CM, Ridway JBB, Henner D, Wong WLT, Rowland AM, Kotts C, Carver ME and Shepard HM (1992) Humanization of an anti-p 185HER2 antibody for human cancer therapy. Proc Natl Acad Sci USA 89: 4285–4289
Cobleigh MA, Vogel CL, Tripathy D, Robert NJ, Scholl S, Fehrenbacher L, Paton V, Shak S, Lieberman G and Slamon D (1998) Efficacy and safety of HERCEPTIN (humanized anti-HER2 antibody) as a single agent in 222 women with HER2 overexpression who relapsed following chemotherapy. Proc ASCO 17: 97
Coussens L, Yang-Feng TL, Liao YC, Chen E, Gray A, McGrath J, Seeberg PhH, Lebermann TA, Schlessinger J, Franke U, Levinson A and Ullrich A (1985) Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with the neu oncogene. Science 230: 1130–1139
Fukushige SI, Matsubara K and Yoshida M (1986) Localisation of a novel verbB-related gene, c-erbB-2, on chromosome-17 and its amplification in a gastric cell line. Mol Cell Biol 6: 955–958
Kita Y, Tseng J, Horan T, Wen J, Philo J, Chang D Ratzkin B, Pacifici R, Branknow D, Hu S, Luo Y, Wen D, Arakawa T and Nicolson M (1996) ErbB receptor activation, cell morphology changes, and apoptosis induced by anti-Her2 monoclonal antibodies. Biochem Biophys Res Commun 226: 59–69
Kurebayashi J, Otsuki T, Yamamoto S, Kurosumi M, Nakata T, Akinaga S and Sonoo H (1998) A pure antioestrogen, ICI 182,780, stimulates the growth of tamoxifen-resistant KPL-1 human breast cancer cells in vivo but not in vitro. Oncology 55S: 23–34
Kurebayashi J, Tang CK, Otsuki T, Kurosumi M, Yamamoto S, Tanaka K, Mochizuki M, Nakamura H and Sonoo H (1999) Isolation and characterisation of a new human breast cancer cell line, KPL-4, expressing Erb B family receptors and interleukin-6. Br J Cancer 79: 707–717
Kuwashima Y, Kobayashi Y, Kawarai A, Uehara T, Kurosumi M, Tanuma J, Shiromizu K, Katsuzawa M and Kishi K (1996) Expression of bcl-2 and apoptotic DNA fragmentation in human endoterial adenocarcinoma cells. Anticancer Res 16: 3221–3224
Lewis GD, Figari I, Fendly B, Wong WL, Carter P, Gorman C and Shepard HM (1993) Differential responses of human tumor cell lines to anti-p 185HER2 monoclonal antibodies. Cancer Immunol Immunother 37: 255–263
McCann AH, Dervan PA, O'Regan M, Codd MB, Gullick WJ, Tobin BMJ and Carney DN (1991) Prognostic significance of c-erbB-2 and estrogen receptor status in human breast cancer. Cancer Res 50: 3296–3303
McLeskey SW, Zhang L, El-Ashry D, Trock BJ, Lopez CA, Kharbanda S, Tobios CA, Lorant LA, Hunnum RS, Dickson RB and Kern FG (1998) Tamoxifen-resistant fibroblast growth factor-transfected MCF-7 cells are cross-resistant in vivo to the antiestrogen ICI 182,780 and two aromatase inhibitors. Clin Cancer Res 4: 497–711
Maguire HC and Greene MI (1989) The neu (c-erbB-2) oncogene. Semin Oncol 16: 148–155
Otsuki T, Yamada O, Sakaguchi H, Tomokuni A, Wada H, Yawata Y and Ueki A (1998) Human myeloma cell apoptosis induced by interferon-alpha. Br J Haematol 103: 518–529
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
Perry RR, King Y and Greaves BR (1995) Relationship between tamoxifen-induced transforming growth factor β1 expression, cytostasis and apoptosis in human breast cancer cells. Br J Cancer 72: 1441–1446
Read LD, Keith D, Slamon DJ and Katzenellenbogen BS (1990) Hormonal modulation of HER2/neu protooncogene messenger ribonucleic acid and p185 protein expression in human breast cancer cell lines. Cancer Res 50: 3947–3951
Ross JS and Fletcher JA (1998) The HER/neu oncogene in breast cancer: prognostic factor, predictive factor, and target for therapy. Stem Cell 16: 413–428
Schecter AL, Stern DF, Vaidyanathan L and Decker SJ (1984) The neu oncogene: an erbB-related gene encoding a 185,000 Mr tumour antigen. Nature 312: 513–516
Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A and McGuire WL (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER2/neu oncogene. Science 235: 177–182
Slamon D, Layland-Jones B, Shak S, Paton V, Bajamonde A, Fleming T, Eiemann W, Wolter J and Norton L (1998) Addition of HERCEPTIN (humanized anti-HER2 antibody) to first line chemotherapy for HER2 overexpressing metastatic breast cancer (HER2+/MBC) markedly increases anticancer activity: a randomized, multinational controlled phase II trial. Proc ASCO 17: 98
Tang CK, Perez C, Grunt T, Waibel C, Cho C and Lupu R (1996) Involvement of heregulin-β2 in the acquisition of the hormone-independent phenotype of breast cancer cells. Cancer Res 56: 3350–3358
Tokuda Y, Ohnishi Y, Shimamura K, Iwasawa M, Yoshimura M, Ueyama Y, Tamaoki N, Tajima T and Mitomi T (1996) In vitro and in vivo anti-tumour effects of a humanised monoclonal antibody against c-erbB-2 product. Br J Cancer 73: 1362–1365
Watts CK, Brady A, Sarcevic B, deFazio A, Musgrove EA and Sutherland RL (1995) Antiestrogen inhibition of cell cycle progression in breast cancer cells in association with inhibition of cyclin-dependent kinase activity and decreased retinoblastoma protein phosphorylation. Mol Endocrinol 9: 1804–1813
Witters LM, Kumar R, Chinchilli VM and Lipton A (1997) Enhanced anti-proliferative activity of the combination of tamoxifen plus HER-2-neu antibody. Breast Cancer Res Treat 42: 1–5
Wright C, Angus B, Nicholson S, Sainsbury JRC, Cairns J, Gullick WJ, Kelly P, Harris AL and Wilson Horne CH (1989) Expression of c-erbB-2 oncoprotein: a prognostic indicator in human breast cancer. Cancer Res 49: 2087–2090
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
Kunisue, H., Kurebayashi, J., Otsuki, T. et al. Anti-HER2 antibody enhances the growth inhibitory effect of anti-oestrogen on breast cancer cells expressing both oestrogen receptors and HER2. Br J Cancer 82, 46–51 (2000). https://doi.org/10.1054/bjoc.1999.0875
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1054/bjoc.1999.0875
Keywords
This article is cited by
-
Optimizing the Use of Neoadjuvant Endocrine Therapy
Current Oncology Reports (2015)
-
Therapeutic Considerations When Treating HER2-positive Metastatic Breast Cancer
Current Breast Cancer Reports (2014)
-
Preclinical study of prolonged administration of trastuzumab as combination therapy after disease progression during trastuzumab monotherapy
Cancer Chemotherapy and Pharmacology (2010)
-
Preclinical rationale for combined use of endocrine therapy and 5-fluorouracil but neither doxorubicin nor paclitaxel in the treatment of endocrine-responsive breast cancer
Cancer Chemotherapy and Pharmacology (2010)
-
Antikörper und Tyrosinkinaseinhibitoren
Der Gynäkologe (2010)