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Updated: Sep 21, 2025
Systems Biology of Metabolic Regulation by Estrogen Receptor Signaling in Breast Cancer
Published on: March 17, 2016
Integrated DNA and RNA Sequencing Reveals Drivers of Endocrine Resistance in Estrogen Receptor-Positive Breast Cancer
Youli Xia1,2,3, Xiaping He3, Lorna Renshaw4
1Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Purpose:
Endocrine therapy resistance (ETR) remains the greatest challenge in treating patients with hormone receptor-positive breast cancer. We set out to identify molecular mechanisms underlying ETR through in-depth genomic analysis of breast tumors.
Experimental Design:
We collected pre-treatment and sequential on-treatment tumor samples from 35 patients with estrogen receptor-positive breast cancer treated with neoadjuvant then adjuvant endocrine therapy; 3 had intrinsic resistance, 19 acquired resistance, and 13 remained sensitive. Response was determined by changes in tumor volume neoadjuvantly and by monitoring for adjuvant recurrence. Twelve patients received two or more lines of endocrine therapy, with subsequent treatment lines being initiated at the time of development of resistance to the previous endocrine therapy. DNA whole-exome sequencing and RNA sequencing were performed on all samples, totalling 169 unique specimens. DNA mutations, copy-number alterations, and gene expression data were analyzed through unsupervised and supervised analyses to identify molecular features related to ETR.
Results:
Mutations enriched in ETR included ESR1 and GATA3. The known ESR1 D538G variant conferring ETR was identified, as was a rarer E380Q variant that confers endocrine hypersensitivity. Resistant tumors which acquired resistance had distinct gene expression profiles compared with paired sensitive tumors, showing elevated pathways including ER, HER2, GATA3, AKT, RAS, and p63 signaling. Integrated analysis in individual patients highlighted the diversity of ETR mechanisms.
Conclusions:
The mechanisms underlying ETR are multiple and characterized by diverse changes in both somatic genetic and transcriptomic profiles; to overcome resistance will require an individualized approach utilizing genomic and genetic biomarkers and drugs tailored to each patient.
Insights
Endocrine therapy resistance in breast cancer involves diverse genomic and transcriptomic changes. Overcoming this challenge requires personalized treatment strategies based on individual patient biomarkers.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Endocrine therapy resistance (ETR) is a major obstacle in treating hormone receptor-positive breast cancer.
- Understanding the molecular underpinnings of ETR is crucial for developing effective treatments.
Purpose of the Study:
- To identify molecular mechanisms driving ETR in breast cancer.
- To analyze genomic and transcriptomic profiles of tumors from patients with varying responses to endocrine therapy.
Main Methods:
- Whole-exome and RNA sequencing of 169 tumor samples from 35 patients with estrogen receptor-positive breast cancer.
- Analysis of DNA mutations, copy-number alterations, and gene expression.
- Comparison of molecular profiles between resistant and sensitive tumors.
Main Results:
- Enrichment of ESR1 and GATA3 mutations in ETR, including known (D538G) and novel (E380Q) ESR1 variants.
- Distinct gene expression profiles in acquired resistance, with elevated ER, HER2, GATA3, AKT, RAS, and p63 signaling pathways.
- Identification of diverse ETR mechanisms through integrated patient-level analysis.
Conclusions:
- ETR is driven by multiple, diverse somatic genetic and transcriptomic alterations.
- An individualized approach using genomic biomarkers and tailored drugs is necessary to overcome resistance.
