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Updated: Nov 30, 2025
Systems Biology of Metabolic Regulation by Estrogen Receptor Signaling in Breast Cancer
Published on: March 17, 2016
Steroid Hormone Receptor and Infiltrating Immune Cell Status Reveals Therapeutic Vulnerabilities of ESR1-Mutant
Michelle M Williams1, Nicole S Spoelstra1, Spencer Arnesen2
1Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
Abstract:
Mutations in ESR1 that confer constitutive estrogen receptor alpha (ER) activity in the absence of ligand are acquired by ≥40% of metastatic breast cancers (MBC) resistant to adjuvant aromatase inhibitor (AI) therapy. To identify targetable vulnerabilities in MBC, we examined steroid hormone receptors and tumor-infiltrating immune cells in metastatic lesions with or without ER mutations. ER and progesterone receptor (PR) were significantly lower in metastases with wild-type (WT) ER compared with those with mutant ER, suggesting that metastases that evade AI therapy by mechanism(s) other than acquiring ER mutations lose dependency on ER and PR. Metastases with mutant ER had significantly higher T regulatory and Th cells, total macrophages, and programmed death ligand-1 (PD-L1)-positive immune-suppressive macrophages than those with WT ER. Breast cancer cells with CRISPR-Cas9-edited ER (D538G, Y537S, or WT) and patient-derived xenografts harboring mutant or WT ER revealed genes and proteins elevated in mutant ER cells, including androgen receptor (AR), chitinase-3-like protein 1 (CHI3L1), and IFN-stimulated genes (ISG). Targeting these proteins blunted the selective advantage of ER-mutant tumor cells to survive estrogen deprivation, anchorage independence, and invasion. Thus, patients with mutant ER MBC might respond to standard-of-care fulvestrant or other selective ER degraders when combined with AR or CHI3L1 inhibition, perhaps with the addition of immunotherapy. SIGNIFICANCE: Targetable alterations in MBC, including AR, CHI3L1, and ISG, arise following estrogen-deprivation, and ER-mutant metastases may respond to immunotherapies due to elevated PD-L1+ macrophages.See related article by Arnesen et al., p. 539.
Insights
Mutations in estrogen receptor alpha (ER) drive resistance to aromatase inhibitor therapy in metastatic breast cancer (MBC). Targeting androgen receptor (AR), CHI3L1, or IFN-stimulated genes (ISG) may overcome this resistance, potentially with immunotherapy.
Area of Science:
- Oncology
- Endocrinology
- Immunology
Background:
- Over 40% of metastatic breast cancers (MBC) develop resistance to aromatase inhibitor (AI) therapy through acquired mutations in estrogen receptor alpha (ER).
- These ESR1 mutations confer ligand-independent ER activity, driving cancer growth despite AI treatment.
- Understanding resistance mechanisms is crucial for developing effective therapies for advanced breast cancer.
Purpose of the Study:
- To identify targetable vulnerabilities in ER-mutant metastatic breast cancer (MBC) resistant to AI therapy.
- To investigate the role of steroid hormone receptors and immune cell infiltration in ER-mutant versus wild-type (WT) ER metastases.
- To explore novel therapeutic strategies targeting identified alterations in ER-mutant MBC.
Main Methods:
- Analysis of steroid hormone receptors (ER, PR) and tumor-infiltrating immune cells in metastatic lesions from MBC patients with and without ER mutations.
- Utilized CRISPR-Cas9 gene editing to create ER mutant (D538G, Y537S) and WT ER breast cancer cells.
- Employed patient-derived xenografts (PDX) harboring mutant or WT ER to validate findings and test therapeutic interventions.
Main Results:
- Metastases with mutant ER showed significantly lower ER and progesterone receptor (PR) levels compared to WT ER.
- Mutant ER metastases exhibited increased T regulatory cells, Th cells, total macrophages, and PD-L1-positive immunosuppressive macrophages.
- Elevated expression of androgen receptor (AR), chitinase-3-like protein 1 (CHI3L1), and IFN-stimulated genes (ISG) was observed in mutant ER cells.
- Targeting AR, CHI3L1, or ISG reduced the survival advantage of ER-mutant cells under estrogen deprivation and invasion conditions.
Conclusions:
- Targetable alterations including AR, CHI3L1, and ISG emerge in MBC following estrogen deprivation, particularly in ER-mutant tumors.
- ER-mutant MBC may benefit from combination therapies involving selective ER degraders (e.g., fulvestrant) with AR or CHI3L1 inhibitors.
- The increased presence of PD-L1+ macrophages in ER-mutant tumors suggests potential efficacy of immunotherapy in this subset of patients.
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