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

Stefan Prekovic*, 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 for this work

Research output: Contribution to journalArticleAcademicpeer-review

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
JournalEMBO Molecular Medicine
Volume15
Issue number12
Early online date30 Oct 2023
DOIs
Publication statusPublished - 7 Dec 2023

Keywords

  • breast cancer
  • glucocorticoids
  • luminal breast cancer subtypes
  • nuclear receptors
  • ZBTB16

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