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. 1995 Dec;96(6):2775–2782. doi: 10.1172/JCI118347

Breast cancer selective gene expression and therapy mediated by recombinant adenoviruses containing the DF3/MUC1 promoter.

L Chen 1, D Chen 1, Y Manome 1, Y Dong 1, H A Fine 1, D W Kufe 1
PMCID: PMC185987  PMID: 8675647

Abstract

The high molecular weight mucin-like glycoprotein, DF3 (MUC1), is overexpressed in the majority of human breast cancers. Here we demonstrate that replication defective recombinant adenoviral vectors, containing the DF3 promoter (bp -725 to +31), can be used to express beta-galactosidase (Ad.DF3-betagal) and the herpes simplex virus thymidine kinase (HSV-tk) gene (Ad.Df3-tk) in DF3 positive breast carcinoma cell lines. In vivo experiments using breast tumor implants in nude mice injected with Ad.DF3-betagal demonstrated that expression of the beta-galactosidase gene is limited to DF3-positive breast cancer xenografts. Moreover, in an intraperitoneal breast cancer metastases model, we show that i.p. injection of Ad.DF3-tk followed by GCV treatment results in inhibition of tumor growth. These results demonstrate that utilization of the DF3 promoter in an adenoviral vector can confer selective expression of heterologous genes in breast cancer cells in vitro and in vivo.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abe M., Kufe D. Characterization of cis-acting elements regulating transcription of the human DF3 breast carcinoma-associated antigen (MUC1) gene. Proc Natl Acad Sci U S A. 1993 Jan 1;90(1):282–286. doi: 10.1073/pnas.90.1.282. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Abe M., Kufe D. Transcriptional regulation of DF3 gene expression in human MCF-7 breast carcinoma cells. J Cell Physiol. 1990 May;143(2):226–231. doi: 10.1002/jcp.1041430205. [DOI] [PubMed] [Google Scholar]
  3. Bett A. J., Haddara W., Prevec L., Graham F. L. An efficient and flexible system for construction of adenovirus vectors with insertions or deletions in early regions 1 and 3. Proc Natl Acad Sci U S A. 1994 Sep 13;91(19):8802–8806. doi: 10.1073/pnas.91.19.8802. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chen L., Waxman D. J. Intratumoral activation and enhanced chemotherapeutic effect of oxazaphosphorines following cytochrome P-450 gene transfer: development of a combined chemotherapy/cancer gene therapy strategy. Cancer Res. 1995 Feb 1;55(3):581–589. [PubMed] [Google Scholar]
  5. Colbere-Garapin F., Chousterman S., Horodniceanu F., Kourilsky P., Garapin A. C. Cloning of the active thymidine kinase gene of herpes simplex virus type 1 in Escherichia coli K-12. Proc Natl Acad Sci U S A. 1979 Aug;76(8):3755–3759. doi: 10.1073/pnas.76.8.3755. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Crystal R. G., McElvaney N. G., Rosenfeld M. A., Chu C. S., Mastrangeli A., Hay J. G., Brody S. L., Jaffe H. A., Eissa N. T., Danel C. Administration of an adenovirus containing the human CFTR cDNA to the respiratory tract of individuals with cystic fibrosis. Nat Genet. 1994 Sep;8(1):42–51. doi: 10.1038/ng0994-42. [DOI] [PubMed] [Google Scholar]
  7. Culver K. W., Ram Z., Wallbridge S., Ishii H., Oldfield E. H., Blaese R. M. In vivo gene transfer with retroviral vector-producer cells for treatment of experimental brain tumors. Science. 1992 Jun 12;256(5063):1550–1552. doi: 10.1126/science.1317968. [DOI] [PubMed] [Google Scholar]
  8. Culver K., Cornetta K., Morgan R., Morecki S., Aebersold P., Kasid A., Lotze M., Rosenberg S. A., Anderson W. F., Blaese R. M. Lymphocytes as cellular vehicles for gene therapy in mouse and man. Proc Natl Acad Sci U S A. 1991 Apr 15;88(8):3155–3159. doi: 10.1073/pnas.88.8.3155. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Dranoff G., Jaffee E., Lazenby A., Golumbek P., Levitsky H., Brose K., Jackson V., Hamada H., Pardoll D., Mulligan R. C. Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3539–3543. doi: 10.1073/pnas.90.8.3539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Engelhardt J. F., Ye X., Doranz B., Wilson J. M. Ablation of E2A in recombinant adenoviruses improves transgene persistence and decreases inflammatory response in mouse liver. Proc Natl Acad Sci U S A. 1994 Jun 21;91(13):6196–6200. doi: 10.1073/pnas.91.13.6196. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Ezzeddine Z. D., Martuza R. L., Platika D., Short M. P., Malick A., Choi B., Breakefield X. O. Selective killing of glioma cells in culture and in vivo by retrovirus transfer of the herpes simplex virus thymidine kinase gene. New Biol. 1991 Jun;3(6):608–614. [PubMed] [Google Scholar]
  12. Graham F. L., Smiley J., Russell W. C., Nairn R. Characteristics of a human cell line transformed by DNA from human adenovirus type 5. J Gen Virol. 1977 Jul;36(1):59–74. doi: 10.1099/0022-1317-36-1-59. [DOI] [PubMed] [Google Scholar]
  13. Hackett A. J., Smith H. S., Springer E. L., Owens R. B., Nelson-Rees W. A., Riggs J. L., Gardner M. B. Two syngeneic cell lines from human breast tissue: the aneuploid mammary epithelial (Hs578T) and the diploid myoepithelial (Hs578Bst) cell lines. J Natl Cancer Inst. 1977 Jun;58(6):1795–1806. doi: 10.1093/jnci/58.6.1795. [DOI] [PubMed] [Google Scholar]
  14. Haj-Ahmad Y., Graham F. L. Characterization of an adenovirus type 5 mutant carrying embedded inverted terminal repeats. Virology. 1986 Aug;153(1):22–34. doi: 10.1016/0042-6822(86)90004-8. [DOI] [PubMed] [Google Scholar]
  15. Harris J. D., Gutierrez A. A., Hurst H. C., Sikora K., Lemoine N. R. Gene therapy for cancer using tumour-specific prodrug activation. Gene Ther. 1994 May;1(3):170–175. [PubMed] [Google Scholar]
  16. Herz J., Gerard R. D. Adenovirus-mediated transfer of low density lipoprotein receptor gene acutely accelerates cholesterol clearance in normal mice. Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):2812–2816. doi: 10.1073/pnas.90.7.2812. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Huard J., Lochmüller H., Acsadi G., Jani A., Massie B., Karpati G. The route of administration is a major determinant of the transduction efficiency of rat tissues by adenoviral recombinants. Gene Ther. 1995 Mar;2(2):107–115. [PubMed] [Google Scholar]
  18. Huber B. E., Austin E. A., Good S. S., Knick V. C., Tibbels S., Richards C. A. In vivo antitumor activity of 5-fluorocytosine on human colorectal carcinoma cells genetically modified to express cytosine deaminase. Cancer Res. 1993 Oct 1;53(19):4619–4626. [PubMed] [Google Scholar]
  19. Huber B. E., Richards C. A., Krenitsky T. A. Retroviral-mediated gene therapy for the treatment of hepatocellular carcinoma: an innovative approach for cancer therapy. Proc Natl Acad Sci U S A. 1991 Sep 15;88(18):8039–8043. doi: 10.1073/pnas.88.18.8039. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Jaffee E. M., Dranoff G., Cohen L. K., Hauda K. M., Clift S., Marshall F. F., Mulligan R. C., Pardoll D. M. High efficiency gene transfer into primary human tumor explants without cell selection. Cancer Res. 1993 May 15;53(10 Suppl):2221–2226. [PubMed] [Google Scholar]
  21. Kass-Eisler A., Falck-Pedersen E., Elfenbein D. H., Alvira M., Buttrick P. M., Leinwand L. A. The impact of developmental stage, route of administration and the immune system on adenovirus-mediated gene transfer. Gene Ther. 1994 Nov;1(6):395–402. [PubMed] [Google Scholar]
  22. Kovarik A., Peat N., Wilson D., Gendler S. J., Taylor-Papadimitriou J. Analysis of the tissue-specific promoter of the MUC1 gene. J Biol Chem. 1993 May 5;268(13):9917–9926. [PubMed] [Google Scholar]
  23. Kufe D., Inghirami G., Abe M., Hayes D., Justi-Wheeler H., Schlom J. Differential reactivity of a novel monoclonal antibody (DF3) with human malignant versus benign breast tumors. Hybridoma. 1984 Fall;3(3):223–232. doi: 10.1089/hyb.1984.3.223. [DOI] [PubMed] [Google Scholar]
  24. Manome Y., Abe M., Hagen M. F., Fine H. A., Kufe D. W. Enhancer sequences of the DF3 gene regulate expression of the herpes simplex virus thymidine kinase gene and confer sensitivity of human breast cancer cells to ganciclovir. Cancer Res. 1994 Oct 15;54(20):5408–5413. [PubMed] [Google Scholar]
  25. Moolten F. L., Wells J. M. Curability of tumors bearing herpes thymidine kinase genes transferred by retroviral vectors. J Natl Cancer Inst. 1990 Feb 21;82(4):297–300. doi: 10.1093/jnci/82.4.297. [DOI] [PubMed] [Google Scholar]
  26. Mullen C. A., Kilstrup M., Blaese R. M. Transfer of the bacterial gene for cytosine deaminase to mammalian cells confers lethal sensitivity to 5-fluorocytosine: a negative selection system. Proc Natl Acad Sci U S A. 1992 Jan 1;89(1):33–37. doi: 10.1073/pnas.89.1.33. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Nabel E. G., Gordon D., Yang Z. Y., Xu L., San H., Plautz G. E., Wu B. Y., Gao X., Huang L., Nabel G. J. Gene transfer in vivo with DNA-liposome complexes: lack of autoimmunity and gonadal localization. Hum Gene Ther. 1992 Dec;3(6):649–656. doi: 10.1089/hum.1992.3.6-649. [DOI] [PubMed] [Google Scholar]
  28. Nabel E. G., Plautz G., Nabel G. J. Site-specific gene expression in vivo by direct gene transfer into the arterial wall. Science. 1990 Sep 14;249(4974):1285–1288. doi: 10.1126/science.2119055. [DOI] [PubMed] [Google Scholar]
  29. Nolan G. P., Fiering S., Nicolas J. F., Herzenberg L. A. Fluorescence-activated cell analysis and sorting of viable mammalian cells based on beta-D-galactosidase activity after transduction of Escherichia coli lacZ. Proc Natl Acad Sci U S A. 1988 Apr;85(8):2603–2607. doi: 10.1073/pnas.85.8.2603. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. O'Malley B. W., Jr, Chen S. H., Schwartz M. R., Woo S. L. Adenovirus-mediated gene therapy for human head and neck squamous cell cancer in a nude mouse model. Cancer Res. 1995 Mar 1;55(5):1080–1085. [PubMed] [Google Scholar]
  31. Ram Z., Culver K. W., Walbridge S., Blaese R. M., Oldfield E. H. In situ retroviral-mediated gene transfer for the treatment of brain tumors in rats. Cancer Res. 1993 Jan 1;53(1):83–88. [PubMed] [Google Scholar]
  32. Smythe W. R., Hwang H. C., Amin K. M., Eck S. L., Davidson B. L., Wilson J. M., Kaiser L. R., Albelda S. M. Use of recombinant adenovirus to transfer the herpes simplex virus thymidine kinase (HSVtk) gene to thoracic neoplasms: an effective in vitro drug sensitization system. Cancer Res. 1994 Apr 15;54(8):2055–2059. [PubMed] [Google Scholar]
  33. Vile R. G., Hart I. R. In vitro and in vivo targeting of gene expression to melanoma cells. Cancer Res. 1993 Mar 1;53(5):962–967. [PubMed] [Google Scholar]
  34. Vile R. G., Hart I. R. Use of tissue-specific expression of the herpes simplex virus thymidine kinase gene to inhibit growth of established murine melanomas following direct intratumoral injection of DNA. Cancer Res. 1993 Sep 1;53(17):3860–3864. [PubMed] [Google Scholar]
  35. Wei M. X., Tamiya T., Chase M., Boviatsis E. J., Chang T. K., Kowall N. W., Hochberg F. H., Waxman D. J., Breakefield X. O., Chiocca E. A. Experimental tumor therapy in mice using the cyclophosphamide-activating cytochrome P450 2B1 gene. Hum Gene Ther. 1994 Aug;5(8):969–978. doi: 10.1089/hum.1994.5.8-969. [DOI] [PubMed] [Google Scholar]
  36. Wilson J. M., Grossman M., Raper S. E., Baker J. R., Jr, Newton R. S., Thoene J. G. Ex vivo gene therapy of familial hypercholesterolemia. Hum Gene Ther. 1992 Apr;3(2):179–222. doi: 10.1089/hum.1992.3.2-179. [DOI] [PubMed] [Google Scholar]
  37. Wolff J. A., Malone R. W., Williams P., Chong W., Acsadi G., Jani A., Felgner P. L. Direct gene transfer into mouse muscle in vivo. Science. 1990 Mar 23;247(4949 Pt 1):1465–1468. doi: 10.1126/science.1690918. [DOI] [PubMed] [Google Scholar]
  38. Wu G. Y., Wilson J. M., Shalaby F., Grossman M., Shafritz D. A., Wu C. H. Receptor-mediated gene delivery in vivo. Partial correction of genetic analbuminemia in Nagase rats. J Biol Chem. 1991 Aug 5;266(22):14338–14342. [PubMed] [Google Scholar]
  39. Wu G. Y., Wu C. H. Receptor-mediated gene delivery and expression in vivo. J Biol Chem. 1988 Oct 15;263(29):14621–14624. [PubMed] [Google Scholar]

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