Data from Steroid Hormone Receptor and Infiltrating Immune Cell Status Reveals Therapeutic Vulnerabilities of ESR1-Mutant Breast Cancer
Year: 2023
Type: other
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
Authors: Michelle M. Williams, Nicole S. Spoelstra, Spencer Arnesen, Kathleen I. O'Neill, Jessica L. Christenson, Jordan Reese, Kathleen C. Torkko, Andrew Goodspeed, Emmanuel Rosas, Toru Hanamura, Sharon B. Sams, Zheqi Li, Steffi Oesterreich, Rebecca B. Riggins, Britta M. Jacobsen, Anthony Elias, Jason Gertz, Jennifer K. Richer
Institutions: University of Colorado Anschutz, University of Utah, Huntsman Cancer Institute, University of Colorado Cancer Center, University of Pittsburgh, Magee-Womens Research Institute, UPMC Hillman Cancer Center, University of Pittsburgh Medical Center, Georgetown University Medical Center, Georgetown Lombardi Comprehensive Cancer Center
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Awards: G1309041795, G1332742017, G1565180698, G2040153736, G324030696, G3298087253, G3767889688, G3932503883, G3984744197, Mechanism-based strategies to target ER-mutant endocrine resistant breast cancer, G4119534169, G5029337574, G5850682332, G7289531960, G8590865752, G8632625050, G9000033339, G9000089931, University of Colorado Cancer Center Support Grant, G9001225491
OpenAlex ID: W4361810471