Luminal breast cancer identity is determined by loss of glucocorticoid receptor activity

Stefan Prekovic (Corresponding author), Theofilos Chalkiadakis, Merel Roest, Daniel Roden, Catrin Lutz, Karianne Schuurman, Mark Opdam, Liesbeth Hoekman, Nina Abbott, Tanja Tesselaar, Maliha Wajahat, Amy R. Dwyer, Isabel Mayayo-Peralta, Gabriela Gomez, Maarten Altelaar, Roderick Beijersbergen, Balázs Győrffy, Leonie Young, Sabine Linn, Jos JonkersWayne Tilley, Theresa Hickey, Damir Vareslija, Alexander Swarbrick, Wilbert Zwart (Corresponding author)

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Abstract

Glucocorticoid receptor (GR) is a transcription factor that plays a crucial role in cancer biology. In this study, we utilized an in silico-designed GR activity signature to demonstrate that GR relates to the proliferative capacity of numerous primary cancer types. In breast cancer, the GR activity status determines luminal subtype identity and has implications for patient outcomes. We reveal that GR engages with estrogen receptor (ER), leading to redistribution of ER on the chromatin. Notably, GR activation leads to upregulation of the ZBTB16 gene, encoding for a transcriptional repressor, which controls growth in ER-positive breast cancer and associates with prognosis in luminal A patients. In relation to ZBTB16's repressive nature, GR activation leads to epigenetic remodeling and loss of histone acetylation at sites proximal to cancer-driving genes. Based on these findings, epigenetic inhibitors reduce viability of ER-positive breast cancer cells that display absence of GR activity. Our findings provide insights into how GR controls ER-positive breast cancer growth and may have implications for patients' prognostication and provide novel therapeutic candidates for breast cancer treatment.

Original languageEnglish
Article numbere17737
Number of pages17
JournalEMBO Molecular Medicine
Volume15
Issue number12
DOIs
Publication statusPublished - 7 Dec 2023

Funding

This work was funded by the Netherlands Organization for Scientific Research NWO VIDI grant 91716401, an Alpe d'Huzes/KWF Bas Mulder Award, KWF grant #12128, and Oncode Institute. BG was supported by the NVKP_16-1-2016-0037 grant. DM was supported by the Breast Cancer Now Fellowship Award, Walk the Walk (2019-08-SF1310), and Science Foundation Ireland (20/FFP-P/8597). MA and LH are supported by the Dutch NWO X-omics Initiative. We would like to acknowledge the NKI-AVL Core Facility Molecular Pathology & Biobanking (CFMPB) for lab support, the NKI Genomics Core Facility for Illumina sequencing and bioinformatics support, and the NKI mouse intervention unit for performing xenograft experiments. We thank Sarah Vahed for proofreading.

FundersFunder number
NKI-AVL Core Facility Molecular Pathology and Biobanking
Walk the Walk2019‐08‐SF1310
Science Foundation Ireland - SFI20/FFP‐P/8597
Nederlandse Organisatie voor Wetenschappelijk Onderzoek91716401
KWF Kankerbestrijding12128
Oncode Institute

    Keywords

    • breast cancer
    • glucocorticoids
    • luminal breast cancer subtypes
    • nuclear receptors
    • ZBTB16
    • Humans
    • Gene Expression Regulation, Neoplastic
    • Cell Line, Tumor
    • Female
    • Receptors, Glucocorticoid/genetics
    • Breast Neoplasms/genetics
    • Receptors, Estrogen/genetics

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