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 Jonkers; Wayne Tilley; Theresa Hickey; Damir Vareslija; Alexander Swarbrick; Wilbert Zwart

doi:10.15252/emmm.202317737

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 journal › Article › Academic › peer-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 language	English
Article number	e17737
Journal	EMBO Molecular Medicine
Volume	15
Issue number	12
Early online date	30 Oct 2023
DOIs	https://doi.org/10.15252/emmm.202317737
Publication status	Published - 7 Dec 2023

Bibliographical note

Publisher Copyright:
© 2023 Netherlands Cancer Institute. Published under the terms of the CC BY 4.0 license.

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.

Funders	Funder number
NKI-AVL
Walk the Walk	2019‐08‐SF1310
Science Foundation Ireland	20/FFP‐P/8597
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	91716401
KWF Kankerbestrijding	12128
Breast Cancer Now
Oncode Institute

Keywords

breast cancer
glucocorticoids
luminal breast cancer subtypes
nuclear receptors
ZBTB16

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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prekovic-et-al-2023-luminal-breast-cancer-identity-is-determined-by-loss-of-glucocorticoid-receptor-activity (1)Final published version, 3.48 MBLicence: CC BY

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Prekovic, S., Chalkiadakis, T., Roest, M., Roden, D., Lutz, C., Schuurman, K., Opdam, M., Hoekman, L., Abbott, N., Tesselaar, T., Wajahat, M., Dwyer, A. R., Mayayo-Peralta, I., Gomez, G., Altelaar, M., Beijersbergen, R., Győrffy, B., Young, L., Linn, S., ... Zwart, W. (2023). Luminal breast cancer identity is determined by loss of glucocorticoid receptor activity. EMBO Molecular Medicine, 15(12), Article e17737. https://doi.org/10.15252/emmm.202317737

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title = "Luminal breast cancer identity is determined by loss of glucocorticoid receptor activity",

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.",

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month = dec,

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doi = "10.15252/emmm.202317737",

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Prekovic, S, Chalkiadakis, T, Roest, M, Roden, D, Lutz, C, Schuurman, K, Opdam, M, Hoekman, L, Abbott, N, Tesselaar, T, Wajahat, M, Dwyer, AR, Mayayo-Peralta, I, Gomez, G, Altelaar, M, Beijersbergen, R, Győrffy, B, Young, L, Linn, S, Jonkers, J, Tilley, W, Hickey, T, Vareslija, D, Swarbrick, A & Zwart, W 2023, 'Luminal breast cancer identity is determined by loss of glucocorticoid receptor activity', EMBO Molecular Medicine, vol. 15, no. 12, e17737. https://doi.org/10.15252/emmm.202317737

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T1 - Luminal breast cancer identity is determined by loss of glucocorticoid receptor activity

AU - Prekovic, Stefan

AU - Chalkiadakis, Theofilos

AU - Roest, Merel

AU - Roden, Daniel

AU - Lutz, Catrin

AU - Schuurman, Karianne

AU - Opdam, Mark

AU - Hoekman, Liesbeth

AU - Abbott, Nina

AU - Tesselaar, Tanja

AU - Wajahat, Maliha

AU - Dwyer, Amy R.

AU - Mayayo-Peralta, Isabel

AU - Gomez, Gabriela

AU - Altelaar, Maarten

AU - Beijersbergen, Roderick

AU - Győrffy, Balázs

AU - Young, Leonie

AU - Linn, Sabine

AU - Jonkers, Jos

AU - Tilley, Wayne

AU - Hickey, Theresa

AU - Vareslija, Damir

AU - Swarbrick, Alexander

AU - Zwart, Wilbert

PY - 2023/12/7

Y1 - 2023/12/7

N2 - 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.

AB - 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.

KW - breast cancer

KW - glucocorticoids

KW - luminal breast cancer subtypes

KW - nuclear receptors

KW - ZBTB16

UR - http://www.scopus.com/inward/record.url?scp=85175373186&partnerID=8YFLogxK

U2 - 10.15252/emmm.202317737

DO - 10.15252/emmm.202317737

M3 - Article

AN - SCOPUS:85175373186

SN - 1757-4676

VL - 15

JO - EMBO Molecular Medicine

JF - EMBO Molecular Medicine

IS - 12

M1 - e17737

ER -

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

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

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