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Systems Biology of Metabolic Regulation by Estrogen Receptor Signaling in Breast Cancer
Published on: March 17, 2016
Selective Human Estrogen Receptor Partial Agonists (ShERPAs) for Tamoxifen-Resistant Breast Cancer
Rui Xiong1, Hitisha K Patel1, Lauren M Gutgesell1
1Department of Medicinal Chemistry & Pharmacognosy, University of Illinois at Chicago, 833 S Wood St, Chicago, Illinois 60612.
Abstract:
Almost 70% of breast cancers are estrogen receptor α (ERα) positive. Tamoxifen, a selective estrogen receptor modulator (SERM), represents the standard of care for many patients; however, 30-50% develop resistance, underlining the need for alternative therapeutics. Paradoxically, agonists at ERα such as estradiol (E2) have demonstrated clinical efficacy in patients with heavily treated breast cancer, although side effects in gynecological tissues are unacceptable. A drug that selectively mimics the actions of E2 in breast cancer therapy but minimizes estrogenic effects in other tissues is a novel, therapeutic alternative. We hypothesized that a selective human estrogen receptor partial agonist (ShERPA) at ERα would provide such an agent. Novel benzothiophene derivatives with nanomolar potency in breast cancer cell cultures were designed. Several showed partial agonist activity, with potency of 0.8-76 nM, mimicking E2 in inhibiting growth of tamoxifen-resistant breast cancer cell lines. Three ShERPAs were tested and validated in xenograft models of endocrine-independent and tamoxifen-resistant breast cancer, and in contrast to E2, ShERPAs did not cause significant uterine growth.
Insights
New selective human estrogen receptor partial agonists (ShERPAs) show promise for treating tamoxifen-resistant breast cancer. These novel compounds mimic estrogen
Area of Science:
- Oncology
- Endocrinology
- Pharmacology
Background:
- Estrogen receptor alpha (ERα) positive breast cancers (approx. 70%) are often treated with tamoxifen.
- Resistance to tamoxifen develops in 30-50% of patients, necessitating alternative therapies.
- Estradiol (E2) shows efficacy in heavily treated breast cancer but causes unacceptable side effects.
Purpose of the Study:
- To develop a novel therapeutic agent that selectively mimics estrogen's action in breast cancer.
- To identify a drug that minimizes estrogenic side effects in non-target tissues.
- To investigate selective human estrogen receptor partial agonists (ShERPA) as a potential treatment.
Main Methods:
- Design of novel benzothiophene derivatives with nanomolar potency.
- Evaluation of partial agonist activity and inhibition of tamoxifen-resistant breast cancer cell lines.
- Validation of three ShERPAs in xenograft models of endocrine-independent and tamoxifen-resistant breast cancer.
Main Results:
- Several benzothiophene derivatives demonstrated partial agonist activity with potency ranging from 0.8-76 nM.
- These ShERPAs mimicked estradiol (E2) in inhibiting tamoxifen-resistant breast cancer cell growth.
- Tested ShERPAs did not induce significant uterine growth in xenograft models, unlike E2.
Conclusions:
- Selective human estrogen receptor partial agonists (ShERPAs) represent a promising therapeutic strategy.
- ShERPAs effectively inhibit tamoxifen-resistant breast cancer growth.
- These agents offer a potential alternative by selectively targeting breast cancer with reduced gynecological side effects.
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