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

Gene Therapy volume 12, pages 452–460 (2005)Cite this article

A Corrigendum to this article was published on 09 May 2005

An Erratum to this article was published on 09 March 2005

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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Acknowledgements

We are grateful to members of the group for advice and support and to David Peston for immunohistochemical staining. This work was supported by the Charing Cross and Hammersmith Hospitals Trustees, the Prostate Cancer Charity, CR UK, the Wellcome Trust, the AICR, BBSRC and MRC.

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Authors and Affiliations

  1. Department of Cancer Medicine, Imperial College London, London, UK

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

  2. Department of Histopathology, Imperial College London, London, UK

    N Patel

  3. CR UK Children's Cancer Group, Medical Oncology Unit, Queen Mary, University of London, Charterhouse Square, London, UK

    S Shousha

  4. Chester Beatty Laboratories, Leukaemia Research Fund Centre, Institute of Cancer Research, London, UK

    A Zelent

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Buluwela, L., Pike, J., Mazhar, D. et al. Inhibiting estrogen responses in breast cancer cells using a fusion protein encoding estrogen receptor-α and the transcriptional repressor PLZF. Gene Ther 12, 452–460 (2005). https://doi.org/10.1038/sj.gt.3302421

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