¹Department of Biosciences and Nutrition at Novum, Karolinska Institutet, Huddinge, Sweden

Correspondence: C Williams, Department of Biosciences and Nutrition at Novum, Karolinska Institutet, Hälsovägen 7-9, 14157 Huddinge, Sweden. E-mail: cecilia.williams@biosci.ki.se

Received 16 January 2007; Revised 19 June 2007; Accepted 5 July 2007; Published online 13 August 2007.

Abstract

Transcriptional effects of estrogen result from its activation of two estrogen receptor (ER) isoforms; ER that drives proliferation and ER that is antiproliferative. Expression of ER in xenograft tumors from the T47D breast cancer cell line reduces tumor growth and angiogenesis. If ER can halt tumor growth, its introduction into cancers may be a novel therapeutic approach to the treatment of estrogen-responsive cancers. To assess the complete impact of ER on transcription, we have made a full transcriptome analysis of ER- and ER-mediated gene regulation in T47D cell line with Tet-Off regulated ER expression. Of the 35 000 genes and transcripts analysed, 4.1% (1434) were altered by ER activation. Tet withdrawal and subsequent ER expression inhibited the ER regulation of 998 genes and, in addition, altered expression of 152 non-ER-regulated genes. ER-induced and ER-repressed genes were involved in proliferation, steroid/xenobiotic metabolism and ion transport. The ER repressive effect was further confirmed by proliferation assays, where ER was shown to completely oppose the ER–E2 induced proliferation. Additional analysis of ER with a mutated DNA-binding domain revealed that this mutant, at least for a quantity of genes, antagonizes ER even more strongly than ER wt. From an examination of the genes regulated by ER and ER, we suggest that introduction of ER may be an alternative therapeutic approach to the treatment of certain cancers.