Steroid Hormone Receptor and Infiltrating Immune Cell Status Reveals Therapeutic Vulnerabilities of ESR1-Mutant Breast Cancer
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Feb 01, 2021
- Source ID
- 10.1158/0008-5472.can-20-1200
Entities
People
- Andrew Goodspeed
- Anthony D Elias
- Britta Jacobsen
- Emmanuel Rosas
- Jason Gertz
- Jennifer K Richer
- Jessica L Christenson
- Jordan Reese
- Kathleen C. Torkko
- Kathleen I. O’neill
- Michelle M. Williams
- Nicole S. Spoelstra
- Rebecca B Riggins
- Sharon B. Sams
- Spencer Arnesen
- Steffi Oesterreich
- Toru Hanamura
- Zheqi Li
Organizations
- Congressionally Directed Medical Research Programs
- Georgetown University Medical Center
- National Cancer Institute
- National Institutes of Health
- United States Department of Defense
- University of Colorado
- University of Pittsburgh
- University of Utah