Estrogen Receptors as Therapeutic Targets in Breast Cancer
Abstract
The estrogen receptor α (ERα) has proven to be the single most important target in breast cancer over the last 30 years. The use of the selective ER modulator (SERM) tamoxifen for the treatment and prevention of breast cancer has changed therapeutics. The SERM raloxifene, approved for the treatment of osteoporosis, lacks tamoxifens increased risk for endometrial cancer and is being evaluated for the prevention of breast cancer. Other SERMs approved or under development for use against breast cancer or osteoporosis include toremifene, GW5638, GW7604 (the active metabolite of GW5638), idoxifene, lasofoxifene, arzoxifene, bazedoxifene, EM-800 and acolbifene (the active metabolite of EM- 800). Aromatase inhibitors (AIs) have recently proven to be more efficacious than tamoxifen as first-line therapy, efficacious for second-line therapy (e.g. against tamoxifen-resistant disease), and useful for extended adjuvant therapy after tamoxifen. The AIs include the non-steroidal agents letrozole and anastrole, and the steroidal agent exemestane. The pure antiestrogen fulvestrant has proven to be just as effective as AIs. Other pure antiestrogens, ZK-703, ZK-253, RU 58668 and TAS-108 show great promise. The development of resistance to endocrine therapy remains a clinically important problem, and laboratory models based on human breast cancer cells grown as tumors in immune-compromised mice have led to important insights into this problem. Progesterone receptor-negative status of ER-positive breast cancers may reflect altered growth factor receptor signaling, and helps to explain why this subclass of tumors exhibits lower response rates to tamoxifen compared to cancers typed progesterone receptor-positive. Crosstalk among plasma membrane-localized ER, growth factor receptor signaling, and nuclear-localized ER provide further insights into antihormonal-resistant breast cancer. Keywords: Estrogen receptor, selective estrogen receptor modulator, aromatase inhibitor, pure antiestrogen, breast cancer, antihormonal resistance
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The ER in breast cancer and the AR in prostate cancer are the leading examples of targets with well-characterized biological and biochemical properties, clinically validated roles in disease, and previously established clinical efficacy for their inhibition.
“The ER in breast cancer38,39 and the AR in prostate cancer33 are the leading examples of such targets.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [39]
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Bertini, S., Cupertinis, A. D., Granchi, C., Bargagli, B., Tuccinardi, T., Martinelli, A., Macchia, M., Gunther, J. R., Carlson, K. E., Katzenellenbogen, J. A., et al. (2011) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2011.03.030 · Cited by 30 · see citing works
DNA aptamer probes for detection of estrogen receptor α positive carcinomas
Sett, A., Borthakur, B. B., Sharma, J. D., et al. (2016) · Translational research · doi:10.1016/j.trsl.2016.12.008 · Cited by 30 · see citing works
Sesterterpene MHO7 suppresses breast cancer cells as a novel estrogen receptor degrader
Zhao, Y., Zhao, C., Lu, J., et al. (2019) · Pharmacological Research · doi:10.1016/j.phrs.2019.104294 · Cited by 29 · see citing works
Miraghel, S. A., Ebrahimi, N., Khani, L., Mansouri, A., Jafarzadeh, A., Ahmadi, A., & Aref, A. R. (2021) · Pharmacological Research · doi:10.1016/j.phrs.2021.106041 · Cited by 29 · see citing works
- Authors
- Ariazi, E., Ariazi, J., Cordera, F., & Jordan, V.
- ORCID
- Cordera, Fernando
- Venue
- Current Topics in Medicinal Chemistry
- Publisher
- Bentham Science Publishers Ltd.
- Published
- 2006-02-01
- Volume
- 6
- Issue
- 3
- Pages
- 181-202
- ISSN
- 1568-0266 (ISSN-L)
- OpenAlex
- W4254152438
- Cited by
- 255
- References
- 0
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 9 · 2023: 18 · 2022: 16 · 2021: 19 · 2020: 9 · 2019: 14 · 2018: 15 · 2017: 11 · 2016: 13 · 2015: 14 · 2014: 9 · 2013: 12 · 2012: 8
- FWCI
- 10.82
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Current Topics in Medicinal Chemistry (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
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Advanced Breast Cancer Therapies
- Keywords
- estrogen receptor alpha, breast cancer, selective estrogen receptor modulators, tamoxifen, raloxifene, aromatase inhibitors, fulvestrant, endocrine therapy resistance, progesterone receptor-negative breast cancer, growth factor receptor signaling, breast cancer prevention
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