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Updated: Jun 14, 2026
Profiling of Estrogen-regulated MicroRNAs in Breast Cancer Cells
Published on: February 21, 2014
Molecular profiling of aromatase inhibitor sensitive and resistant ER+HER2- postmenopausal breast cancers
Eugene F Schuster1,2, Elena Lopez-Knowles3,4, Anastasia Alataki3,4
1The Breast Cancer Now Toby Robins Research Centre at the Institute of Cancer Research, London, UK. gene.schuster@icr.ac.uk.
Abstract:
Aromatase inhibitors (AIs) reduce recurrences and mortality in postmenopausal patients with oestrogen receptor positive (ER+) breast cancer (BC), but >20% of patients will eventually relapse. Given the limited understanding of intrinsic resistance in these tumours, here we conduct a large-scale molecular analysis to identify features that impact on the response of ER + HER2- BC to AI. We compare the 15% of poorest responders (PRs, n = 177) as measured by proportional Ki67 changes after 2 weeks of neoadjuvant AI to good responders (GRs, n = 190) selected from the top 50% responders in the POETIC trial and matched for baseline Ki67 categories. In this work, low ESR1 levels are associated with poor response, high proliferation, high expression of growth factor pathways and non-luminal subtypes. PRs having high ESR1 expression have similar proportions of luminal subtypes to GRs but lower plasma estradiol levels, lower expression of estrogen response genes, higher levels of tumor infiltrating lymphocytes and immune markers, and more TP53 mutations.
Insights
Aromatase inhibitors help treat estrogen receptor-positive breast cancer, but resistance occurs. Molecular analysis revealed factors linked to poor response, including low ESR1 levels and high proliferation.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Aromatase inhibitors (AIs) are crucial for treating postmenopausal patients with estrogen receptor-positive (ER+) breast cancer (BC).
- However, over 20% of patients experience disease relapse due to intrinsic resistance, necessitating a deeper understanding of resistance mechanisms.
- Limited knowledge exists regarding the molecular features influencing intrinsic resistance to AIs in ER+ HER2- BC.
Purpose of the Study:
- To conduct a large-scale molecular analysis comparing poorest responders (PRs) to good responders (GRs) of neoadjuvant AIs in ER+ HER2- BC.
- To identify molecular features associated with intrinsic resistance and varying response to AIs.
Main Methods:
- Comparison of 177 poorest responders (PRs) with 190 good responders (GRs) from the POETIC trial.
- Selection of PRs from the lowest 15% of responders based on proportional Ki67 changes after 2 weeks of neoadjuvant AI.
- GRs were selected from the top 50% of responders, matched for baseline Ki67 categories.
Main Results:
- Low ESR1 levels were associated with poor response, high proliferation, activated growth factor pathways, and non-luminal subtypes.
- PRs with high ESR1 expression showed similar luminal subtype proportions to GRs.
- These high ESR1 PRs had lower plasma estradiol, reduced estrogen response gene expression, increased tumor-infiltrating lymphocytes and immune markers, and more TP53 mutations.
Conclusions:
- Intrinsic resistance to AIs in ER+ HER2- BC is complex and multifactorial.
- ESR1 expression levels, tumor microenvironment components (lymphocytes, immune markers), and TP53 mutation status are key factors influencing AI response.
- These findings highlight potential therapeutic targets and biomarkers for overcoming AI resistance in breast cancer.
