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Updated: Jul 21, 2025
Systems Biology of Metabolic Regulation by Estrogen Receptor Signaling in Breast Cancer
Published on: March 17, 2016
Revisiting Estrogen for the Treatment of Endocrine-Resistant Breast Cancer: Novel Therapeutic Approaches
Nivida Shete1, Jordan Calabrese1, Debra A Tonetti1
1Department of Pharmaceutical Sciences, University of Illinois Chicago, Chicago, IL 60612, USA.
Abstract:
Estrogen receptor (ER)-positive breast cancer is the most common subtype, representing 70-75% of all breast cancers. Several ER-targeted drugs commonly used include the selective estrogen receptor modulator (SERM), tamoxifen (TAM), aromatase inhibitors (AIs) and selective estrogen receptor degraders (SERDs). Through different mechanisms of action, all three drug classes reduce estrogen receptor signaling. Inevitably, resistance occurs, resulting in disease progression. The counterintuitive action of estrogen to inhibit ER-positive breast cancer was first observed over 80 years ago. High-dose estrogen and diethylstilbestrol (DES) were used to treat metastatic breast cancer accompanied by harsh side effects until the approval of TAM in the 1970s. After the development of TAM, randomized trials comparing TAM to estrogen found similar or slightly inferior efficacy but much better tolerability. After decades of research, it was learned that estrogen induces tumor regression only after a period of long-term estrogen deprivation, and the mechanisms of tumor regression were described. Despite the long history of breast cancer treatment with estrogen, this therapeutic modality is now revitalized due to the development of novel estrogenic compounds with improved side effect profiles, newly discovered predictive biomarkers, the development of non-estrogen small molecules and new combination therapeutic approaches.
Insights
Estrogen therapy, once common for breast cancer, is being revitalized. New estrogenic compounds and combination therapies offer improved efficacy and tolerability for estrogen receptor-positive breast cancer.
Area of Science:
- Oncology
- Endocrinology
- Pharmacology
Background:
- Estrogen receptor (ER)-positive breast cancer is the most prevalent subtype.
- Current ER-targeted therapies include SERMs, AIs, and SERDs, which reduce ER signaling but often lead to resistance.
- Estrogen's paradoxical tumor-inhibiting effect in breast cancer was noted over 80 years ago.
Purpose of the Study:
- To review the historical use of estrogen in breast cancer treatment.
- To explore the mechanisms behind estrogen-induced tumor regression after deprivation.
- To highlight the resurgence of estrogen therapy with novel compounds and strategies.
Main Methods:
- Historical review of estrogen and tamoxifen (TAM) efficacy and tolerability.
- Examination of mechanisms underlying long-term estrogen deprivation-induced tumor regression.
- Analysis of recent advancements in estrogenic compounds, biomarkers, and combination therapies.
Main Results:
- Early high-dose estrogen therapy for metastatic breast cancer had significant side effects.
- Tamoxifen (TAM) demonstrated similar efficacy to estrogen but with better tolerability.
- Estrogen induces tumor regression after prolonged estrogen deprivation, with elucidated mechanisms.
Conclusions:
- Estrogen therapy for ER-positive breast cancer is experiencing a revival.
- Novel estrogenic compounds, predictive biomarkers, and combination approaches enhance therapeutic potential.
- Modern estrogen-based strategies aim for improved efficacy and reduced side effect profiles.
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