A genome-wide study of the repressive effects of estrogen receptor beta on estrogen receptor alpha signaling in breast cancer cells

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