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, Arthur Z Zelent, R. C. Coombes, Simak Ali

Research output: Contribution to journalArticle

10 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Zinc Fingers
Estrogens
Leukemia
Breast Neoplasms
Estrogen Receptors
Gene Expression
Genes
Growth
estrophilin
Cathepsin D
Chromatin Assembly and Disassembly
Response Elements
Progesterone Receptors
Tetracycline
Transcription Factors
Observation
Ligands
Cell Line

Keywords

  • Breast cancer
  • Estrogen receptor
  • Gene expression
  • PLZF

ASJC Scopus subject areas

  • Genetics

Cite this

Inhibiting estrogen responses in breast cancer cells using a fusion protein encoding estrogen receptor-α and the transcriptional repressor PLZF. / 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, Arthur Z; Coombes, R. C.; Ali, Simak.

In: Gene Therapy, Vol. 12, No. 5, 03.2005, p. 452-460.

Research output: Contribution to journalArticle

Buluwela, L, Pike, J, Mazhar, D, Kamalati, T, Hart, SM, Al-Jehani, R, Yahaya, H, Patel, N, Sarwarl, N, Heathcote, DA, Schwickerath, O, Phoenix, F, Hill, R, Aboagye, E, Shousha, S, Waxman, J, Lemoine, NR, Zelent, AZ, Coombes, RC & 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, vol. 12, no. 5, pp. 452-460. https://doi.org/10.1038/sj.gt.3302421
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, Arthur Z ; Coombes, R. C. ; Ali, Simak. / Inhibiting estrogen responses in breast cancer cells using a fusion protein encoding estrogen receptor-α and the transcriptional repressor PLZF. In: Gene Therapy. 2005 ; Vol. 12, No. 5. pp. 452-460.
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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.",
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