1. Inhibiting estrogen responses in breast cancer cells using a fusion protein encoding estrogen receptor-alpha and the transcriptional repressor PLZF.
- Author
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Buluwela L, Pike J, Mazhar D, Kamalati T, Hart SM, Al-Jehani R, Yahaya H, Patel N, Sarwar N, Heathcote DA, Schwickerath O, Phoenix F, Hill R, Aboagye E, Shousha S, Waxman J, Lemoine NR, Zelent A, Coombes RC, and Ali S
- Subjects
- Animals, Cell Line, Tumor, DNA-Binding Proteins metabolism, Estrogen Receptor alpha metabolism, Female, Gene Expression Regulation, Humans, Kruppel-Like Transcription Factors, Luciferases genetics, Mice, Mice, Nude, Promyelocytic Leukemia Zinc Finger Protein, Transcription Factors metabolism, Transfection methods, beta-Galactosidase genetics, Breast Neoplasms metabolism, Breast Neoplasms therapy, DNA-Binding Proteins genetics, Estrogen Receptor alpha genetics, Estrogens metabolism, Genetic Therapy methods, Recombinant Fusion Proteins therapeutic use, Transcription Factors genetics
- Abstract
Estrogen receptor alpha (ERalpha) 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 ERalpha 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 ERalpha 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-ERalpha 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-ERalpha expression is induced, an observation that we have confirmed both in vitro and in vivo. Taken together, these results show that PLZF-ERalpha 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.
- Published
- 2005
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