Inhibiting the glycerophosphodiesterase EDI3 in ER-HER2+ breast cancer cells resistant to HER2-targeted therapy reduces viability and tumour growth

Journal of Experimental & Clinical Cancer Research

Research

Cecilia Lindskog¹  Marcus Schmidt²  Walburgis Brenner²  Katrin Madjar³  Jörg Rahnenführer³  Birte Hellwig³  Jörg Lambert⁴  Mohammad AlWahsh⁵  Cristina Cadenas⁶  Katharina Derksen⁶  Gregor Leonhardt⁶  Defne Göçener⁶  Annika Glotzbach⁶  Simon Lüke⁶  Katharina Rohlf⁶  Jörg Reinders⁶  Özlem Demirci⁶  Nina Overbeck⁶  Jan G. Hengstler⁶  Magdalena Keller⁶  Rosemarie Marchan⁶  Karolina Edlund⁶  Eldar Zent⁷  Mia-Lisa Zischinsky⁷  Matthias Baumann⁷ 

[1] Department of Immunology Genetics and Pathology, Uppsala University, Uppsala, Sweden;Department of Obstetrics and Gynecology, University Medical Center Mainz, Mainz, Germany;Department of Statistics, TU Dortmund University, Dortmund, Germany;Leibniz Institut Für Analytische Wissenschaften - ISAS E.V, Dortmund, Germany;Leibniz Institut Für Analytische Wissenschaften - ISAS E.V, Dortmund, Germany;Institute of Pathology and Medical Research Center (ZMF), University Medical Center Mannheim, Heidelberg University, Mannheim, Germany;Department of Pharmacy, AlZaytoonah University of Jordan, Amman, Jordan;Leibniz Research Centre for Working Environment and Human Factors at the TU Dortmund (IfADo), Ardeystrasse 67, 44139, Dortmund, Germany;Pharmacology Department, Lead Discovery Center, Dortmund, Germany;

关键词: Breast cancer;    HER2 positive breast cancer;    Choline metabolism;    HER2-targeting therapy resistance;    GPCPD1;   

DOI  :  10.1186/s13046-022-02578-w

 received in 2022-06-08, accepted in 2022-12-20,  发布年份 2022

来源: Springer

【 摘 要 】

BackgroundIntrinsic or acquired resistance to HER2-targeted therapy is often a problem when small molecule tyrosine kinase inhibitors or antibodies are used to treat patients with HER2 positive breast cancer. Therefore, the identification of new targets and therapies for this patient group is warranted. Activated choline metabolism, characterized by elevated levels of choline-containing compounds, has been previously reported in breast cancer. The glycerophosphodiesterase EDI3 (GPCPD1), which hydrolyses glycerophosphocholine to choline and glycerol-3-phosphate, directly influences choline and phospholipid metabolism, and has been linked to cancer-relevant phenotypes in vitro. While the importance of choline metabolism has been addressed in breast cancer, the role of EDI3 in this cancer type has not been explored.MethodsEDI3 mRNA and protein expression in human breast cancer tissue were investigated using publicly-available Affymetrix gene expression microarray datasets (n = 540) and with immunohistochemistry on a tissue microarray (n = 265), respectively. A panel of breast cancer cell lines of different molecular subtypes were used to investigate expression and activity of EDI3 in vitro. To determine whether EDI3 expression is regulated by HER2 signalling, the effect of pharmacological inhibition and siRNA silencing of HER2, as well as the influence of inhibiting key components of signalling cascades downstream of HER2 were studied. Finally, the influence of silencing and pharmacologically inhibiting EDI3 on viability was investigated in vitro and on tumour growth in vivo.ResultsIn the present study, we show that EDI3 expression is highest in ER-HER2 + human breast tumours, and both expression and activity were also highest in ER-HER2 + breast cancer cell lines. Silencing HER2 using siRNA, as well as inhibiting HER2 signalling with lapatinib decreased EDI3 expression. Pathways downstream of PI3K/Akt/mTOR and GSK3β, and transcription factors, including HIF1α, CREB and STAT3 were identified as relevant in regulating EDI3 expression. Silencing EDI3 preferentially decreased cell viability in the ER-HER2 + cells. Furthermore, silencing or pharmacologically inhibiting EDI3 using dipyridamole in ER-HER2 + cells resistant to HER2-targeted therapy decreased cell viability in vitro and tumour growth in vivo.ConclusionsOur results indicate that EDI3 may be a potential novel therapeutic target in patients with HER2-targeted therapy-resistant ER-HER2 + breast cancer that should be further explored.

【 授权许可】

CC BY   
© The Author(s) 2023

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