Inhibiting estrogen responses in breast cancer cells using a fusion protein encoding estrogen receptor-α and the transcriptional repressor PLZF

L. Buluwela, J. Pike, D. Mazhar, T. Kamalati, S. M. Hart, R. Al-Jehani, H. Yahaya, N. Patel, N. Sarwarl, D. A. Heathcote, O. Schwickerath, F. Phoenix, R. Hill, E. Aboagye, S. Shousha, J. Waxman, N. R. Lemoine, A. Zelent, R. C. Coombes, Simak Ali

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Estrogen receptor α (ERα) is a ligand-inducible transcription factor that acts to regulate gene expression by binding to palindromic DNA sequence, known as the estrogen response element, in promoters of estrogen-regulated genes. In breast cancer ERα plays a central role, where estrogen-regulated gene expression leads to tumor initiation, growth and survival. As an approach to silencing estrogen-regulated genes, we have studied the activities of a fusion protein between ERα and the promyelocytic leukemia zinc-finger (PLZF) protein, a transcriptional repressor that acts through chromatin remodeling. To do this, we have developed lines from the estrogen-responsive MCF-7 breast cancer cell line in which the expression of the fusion protein PLZF-ERα is conditionally regulated by tetracycline and shows that these feature long-term silencing of the expression of several well-characterized estrogen-regulated genes, namely pS2, cathepsin-D and the progesterone receptor. However, the estrogen-regulated growth of these cells is not inhibited unless PLZF-ERα expression is induced, an observation that we have confirmed both in vitro and in vivo. Taken together, these results show that PLZF-ERα is a potent repressor of estrogen-regulated gene expression and could be useful in distinguishing estrogen-regulated genes required for the growth of breast cancer cells.

Original languageEnglish (US)
Pages (from-to)452-460
Number of pages9
JournalGene Therapy
Volume12
Issue number5
DOIs
StatePublished - Mar 2005

Keywords

  • Breast cancer
  • Estrogen receptor
  • Gene expression
  • PLZF

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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    Buluwela, L., Pike, J., Mazhar, D., Kamalati, T., Hart, S. M., Al-Jehani, R., Yahaya, H., Patel, N., Sarwarl, N., Heathcote, D. A., Schwickerath, O., Phoenix, F., Hill, R., Aboagye, E., Shousha, S., Waxman, J., Lemoine, N. R., Zelent, A., Coombes, R. C., & Ali, S. (2005). Inhibiting estrogen responses in breast cancer cells using a fusion protein encoding estrogen receptor-α and the transcriptional repressor PLZF. Gene Therapy, 12(5), 452-460. https://doi.org/10.1038/sj.gt.3302421