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., and Ali, S.
Estrogen receptora(ERa) 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 ERaplays 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 ERaand 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-ERais 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-ERaexpression is induced, an observation that we have confirmed both in vitro and in vivo. Taken together, these results show that PLZF-ERais 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.Gene Therapy (2005) 12, 452-460. doi:10.1038/sj.gt.3302421 Published online 13 January 2005 [ABSTRACT FROM AUTHOR]