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We showed previously that the hinge region of estrogen receptor (ER) α is involved in mediating its actions. The hinge 1 (H1) ERα mutant has disrupted nuclear localization and has lost interaction with c-JUN, but retains estrogen response element (ERE)–mediated functions. The hinge 2 + nuclear export sequence (H2NES) ERα mutant does not maintain nuclear translocation with hormone and no longer activates ERE target genes but does retain a nongenomic, nonnuclear, rapid-action response. Herein, we used the human endometrial cancer Ishikawa stable cell lines (Ishikawa/vector, Ishikawa/wild-type [WT] ERα, Ishikawa/H1 ERα, or Ishikawa/H2NES ERα) to characterize the biological activities of these 2 ERα hinge region mutants. We confirmed by confocal microscopy increased cytoplasmic ERα in the H1 ERα cell line and full cytoplasmic ERα localization in the H2NES ERα cell line. Luciferase assays using the 3xERE reporter showed activation of H1 ERα and H2NES ERα by estradiol (E2) treatment, but using the endogenous pS2 reporter, luciferase activity was only seen with the H1 ERα cell line. Examining cell proliferation revealed that only the WT ERα and H1 ERα cell lines increased proliferation after treatment. Using microarrays, we found that WT ERα and H1 ERα cluster together, whereas vector and H2NES ERα are most similar and cluster independently of E2 treatment. These studies revealed that the nongenomic activities of ERα are unable to mediate proliferative changes or the transcriptional profile after treatment and demonstrate the importance of genomic action for ERα/E2-mediated responses with the nongenomic actions of ERα being complementary to elicit the full biological actions of ERα.

Research Resource: Comparison of Gene Profiles From Wild-Type ERα and ERα Hinge Region Mutants