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Estrogen receptors similarly mediate the effects of 17β-estradiol on cellular responses but differ in their potencies

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Abstract

17β-estradiol (E2), as the main circulating estrogen hormone, plays critical roles in the physiology and pathophysiology of various tissues. The E2 information is primarily conveyed by the transcription factors, estrogen receptors (ERs) α and β. ERs share similar structural and functional features. Experimental studies indicate that upon binding to E2, ERs directly or indirectly interact with DNA and regulate gene expressions with ERα being more potent transregulator than ERβ. However, studies also showed that ERβ induces alterations in phenotypic features of cancer cell lines independent of E2. These observations suggested that the manner in which the unliganded ERβ induces phenotypic alterations in cancer cell models differs from that of ERα. Studies demonstrated that while requiring E2 for function at low levels of synthesis, the unliganded ERα at augmented concentrations modulates gene expressions and cellular growth. We, therefore, anticipated that heightened levels of ERβ synthesis could similarly circumvent the dependency on E2 leading to gene transcriptions and cellular proliferation. To test this prediction, we used adenovirus-infected cancer cell lines in which ERs were shown to induce genomic and cellular responses. We found that while ERβ at low levels of synthesis was dependent upon E2 for function, the receptor at high levels regulated gene expression and cellular proliferation independent of E2. We then addressed whether ERs at comparable levels that require E2 for function differentially alter gene expressions and cellular responses. We found that ERs mediate the effects of E2 on gene expression, cellular proliferation, apoptosis, and motility with an overlapping pattern. However, ERα was more potent regulator than ERβ in inducing cellular responses. Our results suggest that differences in potencies to regulate the expression of genes are a critical feature of the ER subtypes in mediating E2 signaling in cancer cell lines.

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Acknowledgment

We thank Michelle Zanche and Meghann McBennett of the Functional Genomic Center at the University of Rochester for the incessant guidance, assistance, and execution of qPCR. We are also grateful to Dr. Tim Bushnell and Matthew Cochran of the Cell Separation and Flow Cytometry Facility of the University of Rochester for the supervision and assistance for FACS studies. We thank Mark Gallagher for the critical reading of the manuscript. This study was supported by NIH CA113682 (MM).

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  1. Xiaodong Li

    Present address: NeurogesX, Inc, San Mateo, CA, USA

Authors and Affiliations

  1. Department of Biochemistry and Biophysics, University of Rochester Medical School, Rochester, NY, 14642, USA

    Yanfang Huang, Xiaodong Li & Mesut Muyan

  2. Department of Obstetric and Gynecology, University of Rochester Medical School, Rochester, NY, 14642, USA

    Mesut Muyan

  3. Department of Oncology, University of Rochester Medical School, 601 Elmwood Avenue, Box 712, Rochester, NY, 14642, USA

    Mesut Muyan

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Huang, Y., Li, X. & Muyan, M. Estrogen receptors similarly mediate the effects of 17β-estradiol on cellular responses but differ in their potencies. Endocr 39, 48–61 (2011). https://doi.org/10.1007/s12020-010-9411-8

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