A modified hTERT promoter-directed oncolytic adenovirus replication with concurrent inhibition of TGFΒ signaling for breast cancer therapy

Z. Hu, J. S. Robbins, A. Pister, M. B. Zafar, Z. W. Zhang, J. Gupta, K. J. Lee, K. Neuman, C. O. Yun, T. Guise, P. Seth

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

We were interested in developing oncolytic adenoviral vectors that can be administered systemically for the treatment of breast cancer. To restrict viral replication in breast tumor cells, we constructed mhTERTAd.sTΒRFc, a 01/07-based adenoviral vector expressing the soluble form of transforming growth factor-Β (TGFΒ) receptor II fused with the human Fc IgG1 (sTGFΒRIIFc) gene, in which viral replication is under the control of a modified human telomerase reverse transcriptase (mhTERT) promoter. In addition, mhTERTAd.sTΒRFc-mediated sTGFΒRIIFc production targets the TGFΒ pathway known to contribute to the tumor progression of breast cancer metastasis. We chose to use the mhTERT promoter because it was found to be relatively more active (approximately 20 times) in breast cancer cells compared with normal human cells. We showed that infection of MDA-MB-231 and MCF-7 breast cancer cells for 48 h with mhTERTAd.sTΒRFc produced high levels of sTGFΒRIIFc (greater than 1 g ml 1) in the medium. Breast cancer cells produced nearly a 6000-fold increase in viral titers during the 48 h infection period. However, mhTERTAd.sTΒRFc replication was attenuated in normal cells. Infection of breast cancer cells with a replication-deficient virus Ad(E1-).sTΒRFc also produced high levels of sTGFΒRIIFc, but under these conditions, no detectable viral replication was observed. Adenoviral-mediated production of sTGFΒRIIFc was shown to bind with TGFΒ-1, and to abolish the effects of TGFΒ-1 on downstream SMAD-3 phosphorylation. The administration of mhTERTAd.sTΒRFc intravenously into MDA-MB-231 human xenograft-bearing mice resulted in a significant inhibition of tumor growth and production of sTGFΒRIIFc in the blood. Conversely, intravenous injection of Ad(E1).sTΒRFc did not show a significant inhibition of tumor growth, but resulted in sTGFΒRIIFc in the blood, suggesting that viral replication along with sTGFΒRIIFc protein production is critical in inducing the inhibition of tumor growth. These results warrant future investigation of mhTERTAd.sTΒRFc as an antitumor agent in vivo.

Original languageEnglish (US)
Pages (from-to)235-243
Number of pages9
JournalCancer Gene Therapy
Volume17
Issue number4
DOIs
StatePublished - Apr 1 2010
Externally publishedYes

Keywords

  • Breast cancer
  • Gene therapy
  • Oncolytic adenovirus
  • TERT promoter
  • TGFb

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Cancer Research

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    Hu, Z., Robbins, J. S., Pister, A., Zafar, M. B., Zhang, Z. W., Gupta, J., Lee, K. J., Neuman, K., Yun, C. O., Guise, T., & Seth, P. (2010). A modified hTERT promoter-directed oncolytic adenovirus replication with concurrent inhibition of TGFΒ signaling for breast cancer therapy. Cancer Gene Therapy, 17(4), 235-243. https://doi.org/10.1038/cgt.2009.72