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Updated: Jun 14, 2026
Systems Biology of Metabolic Regulation by Estrogen Receptor Signaling in Breast Cancer
Published on: March 17, 2016
New strategies in estrogen receptor-positive breast cancer
1Department of Medicine, Royal Marsden NHS Foundation Trust, Chelsea, London, United Kingdom. stephen.johnston@rmh.nhs.uk
Abstract:
Endocrine therapy has led to a significant improvement in outcomes for women with estrogen receptor-positive (ER+) breast cancer. Current questions in the adjuvant setting include the optimal duration of endocrine therapy, and the accurate molecular prediction of endocrine responsiveness using gene array-based assays compared with ER expression itself. In advanced disease, novel selective estrogen receptor antagonists (SERM) have failed to make an impact, although the pure ER antagonist fulvestrant may have a role, albeit optimal dose and sequence remain unclear. Overcoming de novo or acquired endocrine resistance remains critical to enhancing further the benefit of existing endocrine therapies. Recent progress has been made in understanding the molecular biology associated with acquired endocrine resistance, including adaptive "cross-talk" between ER and peptide growth factor receptor pathways such as epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor 2 (HER2). Future strategies that are being evaluated include combining endocrine therapy with inhibitors of growth factor receptors or downstream signaling pathways, to treat or prevent critical resistance pathways that become operative in ER+ tumors. Preclinical experiments have provided great promise for this approach, although clinical data remain mixed. Enriching trial recruitment by molecular profiling of different ER+ subtypes will become increasingly important to maximize additional benefit that new agents may bring to current endocrine therapies for breast cancer.
Insights
Endocrine therapy improves outcomes for estrogen receptor-positive (ER+) breast cancer. Strategies to overcome endocrine resistance, like targeting growth factor pathways, show promise but require further clinical validation.
Area of Science:
- Oncology
- Endocrinology
- Molecular Biology
Background:
- Endocrine therapy significantly improves outcomes for estrogen receptor-positive (ER+) breast cancer.
- Optimal duration and molecular prediction of endocrine responsiveness in ER+ breast cancer remain key questions.
- Overcoming endocrine resistance is critical for improving treatment efficacy in advanced ER+ breast cancer.
Purpose of the Study:
- To review current challenges and future strategies in endocrine therapy for ER+ breast cancer.
- To explore the molecular mechanisms of endocrine resistance, including ER and growth factor receptor pathway crosstalk.
- To discuss novel therapeutic approaches combining endocrine therapy with targeted inhibitors.
Main Methods:
- Review of current literature on endocrine therapy for ER+ breast cancer.
- Analysis of molecular mechanisms underlying endocrine resistance.
- Evaluation of preclinical and clinical data for combination therapies.
Main Results:
- Understanding acquired endocrine resistance involves crosstalk between ER and growth factor receptor pathways (e.g., EGFR/HER2).
- Combining endocrine therapy with growth factor receptor inhibitors is a promising strategy to overcome resistance.
- Clinical data for combination therapies are mixed, highlighting the need for molecular profiling in patient selection.
Conclusions:
- Future endocrine therapy for ER+ breast cancer may involve combination strategies targeting resistance pathways.
- Molecular profiling of ER+ subtypes is crucial for enriching clinical trials and maximizing treatment benefits.
- Further research is needed to optimize dosing and sequencing of novel agents like fulvestrant.
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