Abstract
HER-2/neu is overexpressed in 25–30% of human breast cancers. We prepared an anti-HER-2/neu hammerhead ribozyme expressed by a recombinant adenovirus (rAdHER-Rz). Human breast cancer cell lines were transduced with high efficiency, resulting in decreased HER-2/neu expression. In vivo injections of rAdHER-Rz into BT-474 tumors established in nude mice inhibited tumor growth to 20% of mock-treated controls. Similar in vivo effects were shown in MCF-7 cells, which do not overexpress HER-2/neu. The growth inhibitory effects of rAdHER-Rz were greater than those of an antisense-expressing vector. These results suggest the utility of anti-HER-2/neu ribozymes as a rational strategy for gene therapy of breast cancer.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Bargmann CI, Hung MC, Weinberg RA . The neu oncogene encodes an epidermal growth factor receptor-related protein Nature 1986 319: 226–230
Yamamoto T et al. Similarity of protein encoded by the human c-erbB-2 gene to epidermal growth factor receptor Nature 1986 319: 230–234
Di Fiore PP et al. Overexpression of the human EGF receptor confers an EGF-dependent transformed to NIH 3T3 cells Cell 1987 51: 1063–1070
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 1987 84: 7159–7163
Di Fiore PP et al. erbB-2 is a potent oncogene when overexpressed in NIH 3T3 cells Science 1987 237: 178–182
Lonardo F et al. The normal erbB-2 product is an atypical receptor-like tyrosine kinase with constitutive activity in the absence of ligand New Bio 1990 2: 992–1003
Gusterson BA . Identification and interpretation of epidermal growth factor and c-erbB-2 overexpression Eur J Cancer 1992 28: 263–267
Slamon DJ et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer Science 1980 244: 707–712
Slamon DJ et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene Science 1987 235: 177–182
Perren TJ . c-erbB-2 oncogene as a prognostic marker in breast cancer (editorial) Br J Cancer 1991 63: 328–332
Gullick WJ et al. c-erbB-2 protein overexpression in breast cancer is a risk factor in patients with involved and uninvolved lymph nodes Br J Cancer 1991 63: 434–438
Muss HB et al. c-erbB-2 expression and response to adjuvant therapy in women with node-positive early breast cancer New Engl J Med 1994 330: 1260–1266
Pier GN et al. Expression of the p185 encoded by HER2 oncogene in normal and transformed human tissues Int J Cancer 1990 45: 457–461
Press MF, Cordon-Cardo C, Slamon D . Expression of the HER-2/neu proto-oncogene in normal human adult and fetal tissues Oncogene 1990 5: 953–962
Hudziak RM et al. p185HER-2 monoclonal antibody has antiproliferative effects in vitro and sensitized human breast cancer cells to tumor necrosis factor Mol Cell Biol 1989 9: 1165–1172
Fendly BM et al. The extracellular domain of HER2/neu is a potential immunogen for active specific immunotherapy ofbreast cancer Cancer Res 1990 50: 1550–1558
Lewis GD et al. Differential responses of human tumor cell lines to anti-p-185HER-2 monoclonal antibodies Cancer Immunol Immunother 1993 37: 258–263
Valone FH et al. Phase la/lb trial of bispecific antibody MDx-210 in patients with advanced breast or ovarian cancer that overexpress the proto-oncogene HER-2/neu J Clin Oncol 1995 13: 2281–2292
Beerli RR, Wels W, Hynes NE . Intracellular expression of single chain antibodies reverts erb-B2 transformation J Biol Chem 1994 269: 23931–23936
Deshane J et al. Intracellular single-chain antibody directed against erbB2 down-regulated cell surface erbB2 and exhibits a selective anti-proliferative effect in erbB2 overexpressing cancer cell lines Gene Therapy 1994 1: 332–337
Deshane J et al. Intracellular antibody against erbB-2 mediates targeted tumor cell eradication by apoptosis Cancer Gene Ther 1996 3: 89–98
Deshane J et al. Targeted tumor killing via an intracellular antibody against erbB-2 J Clin Invest 1995 96: 2980–2989
Ebbinghaus SW et al. Triplex formation inhibits HER-2/neu transcription in vitro J Clin Invest 1993 92: 2433–2439
Noonberb SB et al. Inhibition of transcription factor binding to the HER2 promoter by triplex-forming oligodeoxyribonucleotides Gene 1994 149: 123–126
Vaughm JP et al. Antisense DNA downregulation of the erbB2 oncogene measured by a flow cytometrick assay Proc Natl Acad Sci USA 1995 92: 8338–8342
Wiechen K, Dietel M . c-erbB-2 antisense phosphorothioate oligodeoxynucleotides inhibit growth and serum-induced cell spreading of p185c-erbB-2 overexpressing ovarian carcinoma cells Intl J Cancer 1995 63: 604–608
Liu X, Pgo B . Inhibition of erbB-2 antisense oligonucleotides Antisense Res Dev 1996 6: 9–16
Kashani-Sabet M, Scanlon KJ . Application of ribozymes to cancer gene therapy Cancer Gene Ther 1995 2: 213–223
Kashani-Sabet M et al. Reversal of the malignant phenotype by an anti-ras ribozyme Antisense Res Dev 1992 2: 3–15
Feng M et al. Neoplastic reversion accomplished by high efficiency adenoviral-mediated delivery of an anti-ras ribozyme Cancer Res 1995 55: 2024–2028
Ohta Y, Kijima H, Kashani-Sabet M, Scanlon KJ . Suppression of the malignant phenotype of melanoma cells by anti-oncogene ribozymes J Invest Derm 1996 106: 275–280
Ohta Y et al. Tissue-specific expression of an anti-ras ribozyme inhibits proliferation of human malignant melanoma cells Nucleic Acids Res 1996 24: 938–942
Kashani-Sabet M et al. Suppression of the neoplastic phenotype in vivo by an anti-ras ribozyme Cancer Res 1994 54: 900–902
Funato T et al. Suppression of H-ras-mediated transformation in HIH3T3 cells by a ras ribozyme Biochem Pharmacol 1994 48: 1471–1475
Czubayko F et al. Adenovirus-mediated transduction of ribozymes abrogates HER-2/neu and pleiotrophin expression and inhibits tumor cell proliferation Gene Therapy 1997 4: 943–949
Juhl H, Downing SG, Wellstein A, Czubayko F . HER-2/neu is rate-limiting for ovarian cancer growth J Biol Chem 1997 272: 29482–29486
Wiechen K, Zimmer C, Dietel M . Selection of a high activity c-erbB-2 ribozyme using a fusion gene of c-erbB-2 and the enhanced green fluorescent protein Cancer Gene Ther 1998 5: 45–51
Anderegg B, Horstmann M, Ernst M, Kabisch H . Transcription of tal-1, a putative oncogene playing an important role in childhood T-ALL, can be shown in normal peripheral blood cells by a highly sensitive RT-PCR assay Pediatr Hematol Oncol 1997 14: 349–358
Nakajima-Lijima S, Hamada H, Reddy P, Takanuga TS . Molecular structure of the human cytooplasmic β-actin gene: intraspecies homology of sequences in the introns Proc Natl Acad Sci USA 1985 82: 6133–6137
Acknowledgements
T Suzuki is supported by the grant from Uehara Memorial Foundation for Research of Life Science, Japan. O Engebraaten is supported by the Norwegian Cancer Society, the US–Norway Fulbright Foundation for Educational Exchange, and the Thomas Fearnley, Heddy and Nils Astrup Foundation. M Kashani-Sabet is supported by the Leaders Society Clinical Career Development Award of the Dermatology Foundation. We thank A Harty for preparing the manuscript. D Curiel is supported by NIH grants ROI-CA60245 and ROI-CA74242.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Suzuki, T., Anderegg, B., Ohkawa, T. et al. Adenovirus-mediated ribozyme targeting of HER-2/neu inhibits in vivo growth of breast cancer cells. Gene Ther 7, 241–248 (2000). https://doi.org/10.1038/sj.gt.3301065
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.gt.3301065
Keywords
This article is cited by
-
pcDNA3.1(−)-mediated ribozyme targeting of HER-2 suppresses breast cancer tumor growth
Molecular Biology Reports (2010)
-
Growth inhibition efficacy of an adenovirus expressing dual therapeutic genes, wild-type p53, and anti-erbB2 ribozyme, against human bladder cancer cells
Cancer Gene Therapy (2006)
-
Gene therapy for carcinoma of the breast
Cancer Gene Therapy (2006)
-
Differential sensitivities of trastuzumab (Herceptin®)-resistant human breast cancer cells to phosphoinositide-3 kinase (PI-3K) and epidermal growth factor receptor (EGFR) kinase inhibitors
Breast Cancer Research and Treatment (2005)
-
Intratumoral administration of an adenovirus expressing a kinase dead form of ErbB-2 inhibits tumor growth
Gene Therapy (2002)