The estrogen receptor (ER)α variant Δ5 exhibits dominant positive activity on ER-regulated promoters in endometrial carcinoma cells

Abstract

Estrogen receptor (ER)α is a ligand-inducible transcription factor that mediates the physiological effects of 17β-estradiol (E2). In the uterus, E2 is involved in tissue growth, maintenance, and differentiation. Δ5ERα (Δ5) is an ERα variant protein expressed in uterine tumors but not in normal tissue. We examined the transcriptional activity of Δ5 and its modulation of human ERα basal and E2-stimulated activity in Ishikawa cells, an endometrial cancer cell line. In transient transfection assays, Δ5 increased basal activity of an estrogen response element-containing promoter in the absence or presence of ERα but lessened stimulation by ERα and E2. Effects of Δ5 were not limited to model reporters, given that cyclin D1 and complement 3 promoters were similarly affected. Increases in basal transcription required dimerization and DNA binding of Δ5, whereas decreased E2 stimulation with ERα required only DNA binding. Decreased ligand stimulation was not unique to E2 but also applied to the selective ER modulators tamoxifen and genistein. However, promoter stimulation by epidermal growth factor is retained with Δ5. The ERα coactivator small nuclear ring finger protein is expressed in Ishikawa cells and uterine tumors, and it enhances effects of Δ5 alone and with ERα on basal activity of an estrogen response element reporter. Thus, in the presence of Δ5 plus ERα, there is a lower transcriptional response to E2 and SERMS, but stimulation by epidermal growth factor is retained. The expression of Δ5 in uterine carcinoma may provide a mechanism by which tumors could maintain expression of E2-responsive genes in the absence of E2.