Estrogen receptors: how do they signal and what are their targets
Abstract
During the past decade there has been a substantial advance in our understanding of estrogen signaling both from a clinical as well as a preclinical perspective. Estrogen signaling is a balance between two opposing forces in the form of two distinct receptors (ER alpha and ER beta) and their splice variants. The prospect that these two pathways can be selectively stimulated or inhibited with subtype-selective drugs constitutes new and promising therapeutic opportunities in clinical areas as diverse as hormone replacement, autoimmune diseases, prostate and breast cancer, and depression. Molecular biological, biochemical, and structural studies have generated information which is invaluable for the development of more selective and effective ER ligands. We have also become aware that ERs do not function by themselves but require a number of coregulatory proteins whose cell-specific expression explains some of the distinct cellular actions of estrogen. Estrogen is an important morphogen, and many of its proliferative effects on the epithelial compartment of glands are mediated by growth factors secreted from the stromal compartment. Thus understanding the cross-talk between growth factor and estrogen signaling is essential for understanding both normal and malignant growth. In this review we focus on several of the interesting recent discoveries concerning estrogen receptors, on estrogen as a morphogen, and on the molecular mechanisms of anti-estrogen signaling.
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ERα and ERβ are estrogen-responsive nuclear receptors that act as transcriptional regulators.
“Whereas ERα and ERβ are estrogen-responsive nuclear receptors that act as transcriptional regulators24,”
From Tamoxifen accelerates the repair of demyelinated lesions in the central nervous system (2016) · cites this paper as [24]
Gonadal steroids can affect cell physiology over the long term by acting as transcription factors to regulate gene expression or rapidly through non-genomic second messenger cascades.
“can affect cell physiology over the long term by acting as transcription factors to regulate gene expression (Heldring et al., 2007) or rapidly through non-genomic second messenger cascades (Micevych and Dominguez, 2009)”
From Does puberty mark a transition in sensitive periods for plasticity in the associative neocortex? (2017) · cites this paper as Heldring et al., 2007
The rise in either androgens or estrogens at puberty in both sexes may activate frontal cortex ERbeta, which may act as a transcription factor to alter gene expression that may then regulate the physiological properties of PV+ interneurons and change network inhibition.
“Thus, the rise in either androgens or estrogens at puberty in both sexes may activate frontal cortex ERbeta where it may act as a transcription factor (Heldring et al., 2007) to alter gene expression that may then regulate the physiological properties of PV+ interneurons and change network inhibition.”
From Does puberty mark a transition in sensitive periods for plasticity in the associative neocortex? (2017) · cites this paper as Heldring et al., 2007
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Notch signaling is required for normal prostatic epithelial cell proliferation and differentiation
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Delage-Mourroux, R., Martini, P. G. V., Choi, I., Kraichely, D. M., Hoeksema, J. N., & Katzenellenbogen, B. S. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m001327200 · Cited by 141 · see citing works
Kurokawa, H., & Arteaga, C. L. (2003) · PubMed · Cited by 139 · see citing works
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Dueñas, M., Luquı́n, S., Chowen, J. A., Torres‐Alemán, I., Naftolin, F. N., & García‐Segura, L. M. (2008) · Neuroendocrinology · doi:10.1159/000126702 · Cited by 136 · see citing works
Gangloff, M., Ruff, M., Eiler, S., Duclaud, S., Wurtz, J., & Moras, D. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m009870200 · Cited by 136 · see citing works
Arai, Y., & Matsumoto, A. (1978) · Psychoneuroendocrinology · doi:10.1016/0306-4530(78)90039-2 · Cited by 135 · see citing works
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Berman, D. M., Desai, N., Wang, X., Karhadkar, S. S., Reynon, M., Abate-Shen, C. T., Beachy, P. A., & Shen, M. M. (2004) · Developmental Biology · doi:10.1016/j.ydbio.2003.11.018 · Cited by 135 · see citing works
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Hormones and endocrine-disrupting chemicals: low-dose effects and nonmonotonic dose responses
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Godoy, P., Hewitt, N. J., Albrecht, U., Andersen, M. E., Ansari, N., Bhattacharya, S., Bode, J. G., Bolleyn, J., Borner, C., Böttger, J., et al. (2013) · Archives of Toxicology · doi:10.1007/s00204-013-1078-5 · Cited by 1,280 · see citing works
Denison, M. S., Soshilov, A. A., He, G., DeGroot, D. E., & Zhao, B. (2011) · Toxicological Sciences · doi:10.1093/toxsci/kfr218 · Cited by 748 · see citing works
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Delfosse, V., Grimaldi, M., Pons, J.-L., Boulahtouf, A., le Maire, A., Cavailles, V., Labesse, G., Bourguet, W., & Balaguer, P. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1203574109 · Cited by 405 · see citing works
The role of androgens and estrogens on healthy aging and longevity
Horstman, A. M., Dillon, E. L., Urban, R. J., & Sheffield-Moore, M. (2012) · The Journals of Gerontology Series A: Biological Sciences and Medical Sciences · doi:10.1093/gerona/gls068 · Cited by 396 · see citing works
Sex differences and sex steroids in lung health and disease
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Effect of Estrogen on Musculoskeletal Performance and Injury Risk
Chidi-Ogbolu, N., & Baar, K. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2018.01834 · Cited by 389 · see citing works
The Influence of Estrogen on Skeletal Muscle: Sex Matters
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The unfolding stories of GPR30, a new membrane-bound estrogen receptor
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Ribas, V., Nguyen, M. T. A., Henstridge, D. C., Nguyen, A.-K., Beaven, S. W., Watt, M. J., & Hevener, A. L. (2010) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00504.2009 · Cited by 309 · see citing works
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Self-citationEnvironmental immune disruptors, inflammation and cancer risk
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The ovarian hormone estradiol plays a crucial role in the control of food intake in females
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Monsivais, D., Dyson, M. T., Yin, P., Coon, J. S., Navarro, A., Feng, G., Malpani, S. S., Ono, M., Ercan, C. M., Wei, J. J., et al. (2014) · Molecular Endocrinology · doi:10.1210/me.2013-1421 · Cited by 91 · see citing works
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“Whereas ER α and ER β are estrogen-responsive nuclear receptors that act as transcriptional regulators 24 , GPR30 is known to modulate several signaling pathways such as the phosphatidylinositol-3 kinase and mitogen-activated protein kinase pathways 25 .”
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Iron acquisition and regulation systems in Streptococcus species
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Most recent strategies targeting estrogen receptor alpha for the treatment of breast cancer
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Multifaceted Interplay between Hormones, Growth Factors and Hypoxia in the Tumor Microenvironment
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Association between single nucleotide polymorphism of the CYP19A1 and ESR2 genes and endometriosis
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- Authors
- Heldring, N., Pike, A., Andersson, S., Matthews, J., Cheng, G., Hartman, J., Tujague, M., Ström, A., Treuter, E., Warner, M., & Gustafsson, J.-Å.
- Affiliations
- Karolinska Institutet (SE)
- Houston Methodist (US)
- ORCID
- Venue
- Physiological Reviews
- Publisher
- American Physiological Society
- Published
- 2007-07
- Volume
- 87
- Issue
- 3
- Pages
- 905-931
- ISSN
- 0031-9333 (ISSN-L)
- 1522-1210
- OpenAlex
- W2121454015
- Cited by
- 1,857
- References
- 338
- Citations by year
- 2026: 53 · 2025: 73 · 2024: 90 · 2023: 88 · 2022: 90 · 2021: 127 · 2020: 80 · 2019: 119 · 2018: 112 · 2017: 122 · 2016: 112 · 2015: 111 · 2014: 120 · 2013: 124 · 2012: 105
- FWCI
- 8.13
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Physiological Reviews (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Effects and risks of endocrine disrupting chemicals
- Keywords
- estrogen receptor, estrogen signaling, estrogen receptor alpha, estrogen receptor beta, splice variants, coregulators, morphogens, breast cancer, prostate cancer, hormone replacement therapy, autoimmune disease, depression
- MeSH terms
- Animals, Estrogens, Female, Humans, Receptors, Estrogen, Signal Transduction, Protein Isoforms
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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