Abstract
HER-2/neu is overexpressed on a variety of human adenocarcinomas and overexpression has been associated with a poor prognosis. For this reason, HER-2 has become an attractive target for immunotherapy. To facilitate testing of anti-HER-2-monoclonal antibodies (MAbs) and immunotoxins (ITs), we have evaluated the in vivo growth and metastatic spread of three HER-2-overexpressing human breast cancer cell lines (BT474, MDA-MB-453 and HCC1954) and one ovarian cancer cell line (SKOV3.ip1) in pre-irradiated male SCID mice using subcutaneous (s.c.), intravenous (i.v.) and intraperitoneal (i.p.) routes of injection. All the cell lines tested grew as s.c. tumors and the growth of BT474 and MDA-MB-453 cells after s.c. injection was improved by co-inoculation with Matrigel. Metastases to the lungs were detectable by PCR or histopathology after s.c. injection of BT474 and to a much lesser extent after s.c. injection of HCC1954, MD-MB-453 and SKOV3.ip1cells. I.P. injection of HCC1954 and SKOV3.ip1 cells produced fatal ascites while i.v. injection of SKOV3.ip1, but not BT474 or MDA-MB-453 cells, resulted in infiltration of lungs and death within 9–11 weeks.
Similar content being viewed by others
References
Coussens L, Yang-Feng TL, Liao YC, Chen E, Gray A, Mc-Grath J, Seeburg PH, Libermann TA, Schlessinger J, Francke U: Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. Science 230: 1132–1139, 1985
Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL: Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235: 177–182, 1987
Di Fiore PP, Pierce JH, Kraus MH, Segatto O, King CR, Aaronson SA: erbB-2 is a potent oncogene when overexpressed in NIH/3T3 cells. Science 237: 178–182, 1987
Hudziak RM, Schlessinger J, Ullrich A: Increased expression of the putative growth factor receptor p185HER2 causes transformation and tumorigenesis of NIH 3T3 cells. Proc Natl Acad Sci USA 84: 7159–7163, 1987
Révillion F, Bonneterre J, Peyrat JP: ERBB2 oncogene in human breast cancer and its clinical significance. Eur J Cancer 34: 791–808, 1998
Press MF, Cordon-Cardo C, Slamon DJ: Expression of the HER-2/neu proto-oncogene in normal human adult and fetal tissues. Oncogene 5: 953–962, 1990
Disis ML, Cheever MA: HER-2/neu protein: A target for antigen-specific immunotherapy of human cancer. Adv Cancer Res 71: 343–371, 1997
King CR, Kasprzyk PG, Fischer PH, Bird RE, Turner NA: Preclinical testing of an anti-erb B-2 recombinant toxin. Breast Cancer Res Treat 38: 19–25, 1996
Baselga J, Tripathy D, Mendelsohn J, Baughman S, Benz CC, Dantis L, Sklarin NT, Seidman AD, Hudis CA, Moore J, Rosen PP, Twaddell T, Henderson IC, Norton L: Phase II study of weekly intravenous recombinant humanized antip185HER2 monoclonal antibody in patients with HER2/neuoverexpressing metastatic breast cancer. J Clin Oncol 14: 737–744, 1996
Harwerth I-M, Wels W, Schlegel J, Muller M, Hynes NE: Monoclonal antibodies directed to the erbB-2 receptor inhibit in vivo tumour cell growth. Br J Cancer 68: 1140–1145, 1993
Pietras RJ, Fendly BM, Chazin VR, Pegram MD, Howell SB, Slamon DJ: Antibody to HER-2/neu receptor blocks DNA repair after cisplatin in human breast and ovarian cancer cells. Oncogene 9: 1829–1838, 1994
Ohnishi Y, Nakamura H, Yoshimura M, Tokuda Y, IwasawaM, Ueyama Y, Tamaoki N, Shimamura K: Prolonged survival of mice with human gastric cancer treated with an anti-c-erbb-2 monoclonal antibody. Br J Cancer 7: 969–973, 1995
King BL, Carter D, Foellmer HG, Kacinski BM: Neu protooncogene amplification and expression in ovarian adenocarcinoma cell lines. Am J Pathol 140: 23–31, 1992
Bosma GC, Fried M, Custer RP, Carroll A, Gibson DM, Bosma MJ: Evidence of functional lymphocytes in some (leaky) SCID mice. J Exp Med 167: 1016–1033, 1988.
Lasfargues EY, Coutinho WG, Redfield ES: Isolation of two human tumor epithelial cell lines from solid breast carcinomas. J Natl Cancer Inst 61: 967–978, 1978
Cailleau R, Young R, Olive M, Reeves WJ, Jr: Breast tumor cell lines from pleural effusions. J Natl Cancer Inst 53: 661–674, 1974
Gazdar AF, Kurvari V, Virmani A, Gollahon L, Sakagucki M, Stasny V, Cunmningham HT, Tomlinson G, Tonk V, Ashfaq R, Wistuba II, Minna JD, Shay JW: Characterization of paired tumor and non-tumor cell lines established from patients with breast cancer. Int J Cancer 78: 766–774, 1998
Yu D, Wolf JK, Scanlon M, Price JE, Hung MC: Enhanced c-erbB-2/neu expression in human ovarian cancer cells correlates with more severe malignancy that can be suppressed by EIA. Cancer Res 53: 891–898, 1993
Tokuda Y, Ohnishi Y, Shimamura K, Iwasawa M, Yoshimura M, Ueyama Y, Tamaoki N, Tajima T, Mitomi T: In vitro and in vivo anti-tumour effects of a humanised monoclonal antibody against c-erbB-2 product. Br J Cancer 73: 1362–1365, 1996
Bai X, Hosler G, Rogers BB, Dawson DB, Scheuermann RH: Quantitative polymerase chain reaction for human herpesvirus diagnosis and measurement of Epstein-Barr virus burden in posttransplant lymphoproliferative disorder. Clin Chem 43: 1843–1849, 1997
Szöllösi J, Balazs M, Feuerstein BG, Benz CC, Waldman FM: ERBB-2 (HER2/neu) gene copy number, p185HER-2 overexpression, and intratumor heterogeneity in human breast cancer. Cancer Res 55: 5400–5407, 1995
Lin YJ, Clinton GM: A soluble protein related to the HER-2 proto-oncogene product is released from human breast carcinoma cells. Oncogene 6: 639–643, 1991
Mori S, Mori Y, Mukaiyama T, Yamada Y, Sonobe Y, Matsushita H, Sakamoto G, Akiyama T, Ogawa M, Shiraishi M, Toyoshima K, Yamamoto T: In vitro and in vivo release of soluble erbB-2 protein from human carcinoma cells. Jpn J Cancer Res 81: 489–494, 1990
Langton BC, Crenshaw MC, Chao LA, Stuart SG, Akita RW, Jackson JE: An antigen immunologically related to the external domain of gp185 is shed from nude mouse tumors overexpressing the c-erbB-2 (HER-2/neu) oncogene. Cancer Res 51: 2593–2597, 1991
Arteaga CL, Hurd SD, Winnier AR, Johnson MD, Fendly BM, Forbes JT: Anti-transforming growth factor (TGF)-β antibodies inhibit breast cancer cell tumorigenicity and increase mouse spleen natural killer cell activity. Implications for a possible role of tumor cell/host TGF-β interactions in human breast cancer progression. J Clin Invest 92: 2569–2576, 1993
Price JE, Polyzos A, Zhang RD, Daniels LM: Tumorigenicity and metastasis of human breast carcinoma cell lines in nude mice. Cancer Res 50: 717–721, 1990
Visonneau S, Cesano A, Torosian MH, Miller EJ, Santoli D: Growth characteristics and metastatic properties of human breast cancer xenografts in immunodeficient mice. Am J Pathol 152: 1299–1311, 1998
Ozzello L, Sordat M: Behavior of tumors produced by transplantation of human mammary cell lines in athymic nude mice. Eur J Cancer 16: 553–559, 1980
De Santes K, Slamon D, Anderson SK, Shepard M, Fendly B, Maneval D, Press O: Radiolabeled antibody targeting of the HER-2/neu oncoprotein. Cancer Res 52: 1916–1923, 1992
Hurwitz E, Stancovski I, Sela M, Yarden Y: 1995. Supression and promotion of tumor growth by monoclonal antibodies to ErbB-2 differentially correlate with cellular uptake. Proc Natl Acad Sci USA 92: 3353–3357, 1995
Yu D, Hung M-C: Expression of activated rat neu oncogene is sufficient to induce experimental metastasis in 3T3 cells. Oncogene 6: 1991–1996, 1991
van Slooten H-J, Bonsing BA, Hiller AJ, Colbern GT, van Dierendonck JH, Cornelisse CJ, Smith HS: Outgrowth of BT-474 human breast cancer cells in immune-deficient mice: A new in vivo model for hormone-dependent breast cancer. Br J Cancer 72: 22–30, 1995
Baselga J, Norton L, Albanell J, Kim Y-M, Mendelson J: 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, 1998
Read LD, Keith D, Slamon DJ, Katzenellenbogen BS: Hormonal modulation of HER-2/neu protooncogene messenger ribonucleic acid and p185 protein expression in human breast cancer cell lines. Cancer Res 50: 3947–3951, 1990
Taverna D, Antoniotti S, Maggiora P, Dati C, De Bortoli M, Hynes NE: erbB-2 expression in estrogen-receptor-positive breast-tumor cell s is regulated by growth-modulatory reagents. Int J Cancer 56: 522–528, 1994
Price JE: Metastasis from human breast cancer cell lines. Breast Cancer Res Treat 39: 93–102, 1996
Mueller BM, Reisfeld RA: Potential of the SCID mouse as a host for human tumors. Cancer Metastasis Rev 10: 193–200, 1991
Xie X, Brünner N, Jensen G, Albrectsen J, Gotthardsen B, Rygaard J: 1992. Comparative studies between nude and SCID mice on the growth and metastatic behavior of xenografted human tumors. Clin Exp Metastasis 10: 201–210, 1992
Mitchell BS, Schumacher U: Use of immunodeficient mice in metastasis research. Br J Biomed Sci 54: 278–286, 1997
Taghian A, Budach W, Zietman A, Freeman J, Gioioso D, Ruka W, Suit HD: Quantitative comparison between the transplantability of human and murine tumors into the subcutaneous tissue of NCr/Sed-nu/nu nude and severe combined immunodeficient mice. Cancer Res 53: 5012–5017, 1993
Mehta RR, Graves JM, Hart GD, Shilkaitis A, Das Gupta TK: Growth and metastasis of human breast carcinoma with Matrigel in athymic mice. Breast Cancer Res Treat 25: 65–71, 1993
Zabrecky JR, Lam T, McKenzie SJ, Carney W: The extracellular domain of p185-neu is released from the surface of human breast carcinoma cells, SK-BR- 3. The J Biol Chem 266: 1716–1720, 1991
Leitzel K, Teramoto Y, Sampson E, Mauceri J, Langton BC, Demers L, Podczaski E, Harvey H, Shambaugh S, Volas G, Weaver S, Lipton A: Elevated soluble c-erbB-2 antigen levels in the serum and effusions of a proportion of breast cancer patients. J Clin Oncol 10: 1436–1443, 1992
Meden H, Marx D, Schauer A, Wuttke W, Kuhn W: Prognostic significance of p105 (c-erbB-2, HER2/neu) serum levels in patients with ovarian cancer. Anticancer Res 17: 757–760, 1997
Krainer M, Brodowicz T, Zeillinger R, Wiltschke C, Seifert M, Kubista E, Zienlinski CC: Tissue expression and serum levels of HER-2/neu in patients with breast cancer. Oncology 54: 475–481, 1997
Brodowicz T, Wiltschke C, Budinsky AC, Krainer M, Steger GG, Zielinski CC: 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, 1997
Kurebayashi J, Nukatsnka M, Fujioka A, Saito, H, and: Postsurgical oral administration of uracil and tegafur inhibits progression of micrometastasis of human breast cancer cells in nude mice. Clin Cancer Res 3: 653–659, 1998
Liu Y, El-Ashry D, Chen D, Ding IYF, Kern FG: MCF-7 breast cancer cells overexpressing transfected c-erbB-2 have an in vitro growth advantage in estrogen-depleted conditions and reduced estrogen-dependence and tamoxifen-sensitivity in vivo. Breast Cancer Res Treat 34: 97–117, 1995
Pegram MD, Finn RS, Arzoo K, Beryt M, Pietras RJ, Slamon DJ: The effect of HER-2/neu overexpression on chemotherapeutic drug sensitivity in human breast and ovarian cancer cells. Oncogene 15: 537–547, 1997
Tan M, J Yao, Yu D: Overexpression of the c-erbB-2 gene enhanced intrinsic metastasis potential in human breast cancer cells without increasing their transformation abilities. Cancer Res 57: 1199–1205, 1997
Smellie WJB, Dean CJ, Sacks NPM, Zalutsky MR, Garg PK, Carnochan P, Eccles SA: Radioimmunotherapy of breast cancer xenografts with monoclonal antibody ICR12 against c-erbB2 p185: Comparison of iodogen and N-succinimidyl 4-methyl-3-(tri-n-butylstannyl) benzoate radioiodination methods. Cancer Res 55: 5842s–5846s, 1995
Zhang RD, Fidler IJ, Price JE: Relative malignant potential of human breast carcinoma cell lines established from pleural effusions and a brain metastasis. Invasion Metastasis 11: 204–215, 1991
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Clinchy, B., Gazdar, A., Rabinovsky, R. et al. The growth and metastasis of human, HER-2/neu-overexpressing tumor cell lines in male SCID mice. Breast Cancer Res Treat 61, 217–228 (2000). https://doi.org/10.1023/A:1006494001861
Issue Date:
DOI: https://doi.org/10.1023/A:1006494001861