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Updated: Aug 28, 2025
Systems Biology of Metabolic Regulation by Estrogen Receptor Signaling in Breast Cancer
Published on: March 17, 2016
Comprehensive Transcriptomic and Proteomic Analyses Identify a Candidate Gene Set in Cross-Resistance for Endocrine
Chung-Liang Li1,2,3, Sin-Hua Moi4, Huei-Shan Lin1,2
1Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80756, Taiwan.
Abstract:
Endocrine therapy (ET) of selective estrogen receptor modulators (SERMs), selective estrogen receptor downregulators (SERDs), and aromatase inhibitors (AIs) has been used as the gold standard treatment for hormone-receptor-positive (HR+) breast cancer. Despite its clinical benefits, approximately 30% of patients develop ET resistance, which remains a major clinical challenge in patients with HR+ breast cancer. The mechanisms of ET resistance mainly focus on mutations in the ER and related pathways; however, other targets still exist from ligand-independent ER reactivation. Moreover, mutations in the ER that confer resistance to SERMs or AIs seldom appear in SERDs. To date, little research has been conducted to identify a critical target that appears in both SERMs/SERDs and AIs. In this study, we conducted comprehensive transcriptomic and proteomic analyses from two cohorts of The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) to identify the critical targets for both SERMs/SERDs and AIs of ET resistance. From a treatment response cohort with treatment response for the initial ET regimen and an endocrine therapy cohort with survival outcomes, we identified candidate gene sets that appeared in both SERMs/SERDs and AIs of ET resistance. The candidate gene sets successfully differentiated progress/resistant groups (PD) from complete response groups (CR) and were significantly correlated with survival outcomes in both cohorts. In summary, this study provides valuable clinical implications for the critical roles played by candidate gene sets in the diagnosis, mechanism, and therapeutic strategy for both SERMs/SERDs and AIs of ET resistance for the future.
Insights
Identifying new targets for endocrine therapy (ET) resistance in hormone-receptor-positive breast cancer is crucial. This study found gene sets that predict resistance to selective estrogen receptor modulators, selective estrogen receptor downregulators, and aromatase inhibitors.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Endocrine therapy (ET) is standard for hormone-receptor-positive (HR+) breast cancer.
- Resistance to ET affects ~30% of patients, posing a significant clinical challenge.
- Current research on ET resistance mechanisms primarily focuses on ER pathway mutations, leaving other targets unexplored.
Purpose of the Study:
- To identify critical molecular targets associated with resistance to multiple ET classes (SERMs, SERDs, AIs).
- To investigate potential shared mechanisms of ET resistance across different drug types.
Main Methods:
- Comprehensive transcriptomic and proteomic analyses were performed on TCGA-BRCA cohorts.
- Two cohorts were utilized: one assessing treatment response and another analyzing survival outcomes.
- Candidate gene sets were identified based on their presence in resistance profiles for SERMs, SERDs, and AIs.
Main Results:
- Identified candidate gene sets that distinguish between progressive/resistant (PD) and complete response (CR) groups.
- These gene sets showed significant correlation with survival outcomes in both patient cohorts.
- The findings suggest shared molecular drivers of resistance across different ET agents.
Conclusions:
- The identified gene sets hold potential as diagnostic biomarkers for ET resistance.
- These findings offer insights into the mechanisms underlying ET resistance.
- The study provides a foundation for developing novel therapeutic strategies targeting ET resistance in HR+ breast cancer.
