Abstract

A new isoform of the human estrogen receptor-alpha (hER-) has been identified and characterized. This 46 kDa isoform (hER46) lacks the N-terminal 173 amino acids present in the previously characterized 66 kDa isoform (hER66). hER46 is encoded by a new class of hER- transcript that lacks the first coding exon (exon 1A) of the ER- gene. We demonstrated that these 1A hER- transcripts originate from the E and F hER- promoters and are produced by the splicing of exon 1E directly to exon 2. Functional analysis of hER46 showed that, in a cell context sensitive to the transactivation function AF-2, this receptor is an effective ligand-inducible transcription factor. In contrast, hER46 is a powerful inhibitor of hER66 in a cell context where the transactivating function of AF-1 predominates over AF-2. The mechanisms by which the AF-1 dominant-negative action is exerted may involve heterodimeri zation of the two receptor isoforms and/or direct competition for the ER- DNA-binding site. hER66/hER46 ratios change with the cell growth status of the breast carcinoma cell line MCF7, suggesting a role of hER46 in cellular proliferation.