Identification of a new isoform of the human estrogen receptor‐alpha (hER‐α) that is encoded by distinct transcripts and that is able to repress hER‐α activation function 1

A new isoform of the human estrogen receptor‐alpha (hER‐α) has been identified and characterized. This 46 kDa isoform (hERα46) lacks the N‐terminal 173 amino acids present in the previously characterized 66 kDa isoform (hERα66). hERα46 is encoded by a new class of hER‐α transcript that lacks the first coding exon (exon 1A) of the ER‐α gene. We demonstrated that these Δ1A hER‐α transcripts originate from the E and F hER‐α promoters and are produced by the splicing of exon 1E directly to exon 2. Functional analysis of hERα46 showed that, in a cell context sensitive to the transactivation function AF‐2, this receptor is an effective ligand‐inducible transcription factor. In contrast, hERα46 is a powerful inhibitor of hERα66 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‐α DNA‐binding site. hERα66/hERα46 ratios change with the cell growth status of the breast carcinoma cell line MCF7, suggesting a role of hERα46 in cellular proliferation.