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Evaluation of a new dual-specificity promoter for selective induction of apoptosis in breast cancer cells

Cancer Gene Therapy volume 8, pages 298–307 (2001)Cite this article

Abstract

The conditional expression of lethal genes in tumor cells is a promising gene therapy approach for the treatment of cancer. The identification of promoters that are preferentially active in cancer cells is the starting point for this strategy. The combination of tissue-specific and tumor-specific elements offers the possibility to artificially develop such promoters. We describe the construction and characterization of a hybrid promoter for transcriptional targeting of breast cancer. In many cases, breast cancer cells retain the expression of estrogen receptors, and most solid tumors suffer from hypoxia as a consequence of their aberrant vascularization. Estrogen response elements and hypoxia-responsive elements were combined to activate transcription in cells that present at least one of these characteristics. When a promoter containing these elements is used to control the expression of the pro-apoptotic gene harakiri, the induction of cell death can be activated by estrogens and hypoxia, and inhibited by antiestrogens such as tamoxifen. Finally, we show evidence that these properties are maintained in the context of an adenoviral vector (AdEHhrk). Therefore, infection with this virus preferentially kills estrogen receptor–positive breast cancer cells, or cells growing under hypoxic conditions. We propose the use of this promoter for transcriptional targeting of breast cancer. Cancer Gene Therapy (2001) 8, 298–307

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Acknowledgements

We thank N. Inohara for the pcDNA3-hrk plasmid, D. Qiang for technical support, the University of Michigan vector core for assistance in the construction of the AdEHhrk virus, and Laurie Kittl for correction of the manuscript. This work was supported by NIH Grants PO1 CA 75136 (to M.C. and G.N.) and CA 67140 (to M.C.).

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Authors and Affiliations

  1. Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, 48109, Michigan

    Ruben Hernandez-Alcoceba, Michael Pihalja & Michael F Clarke

  2. Department of Pathology, University of Michigan Comprehensive Cancer Center, Ann Arbor, 48109, Michigan

    Gabriel Nunez

Authors
  1. Ruben Hernandez-Alcoceba
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  2. Michael Pihalja
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  3. Gabriel Nunez
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  4. Michael F Clarke
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Correspondence to Michael F Clarke.

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Hernandez-Alcoceba, R., Pihalja, M., Nunez, G. et al. Evaluation of a new dual-specificity promoter for selective induction of apoptosis in breast cancer cells. Cancer Gene Ther 8, 298–307 (2001). https://doi.org/10.1038/sj.cgt.7700304

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