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

  1. Keller, Magdalena
  2. Rohlf, Katharina
  3. Glotzbach, Annika ORCID logo
  4. Leonhardt, Gregor ORCID logo
  5. Lüke, Simon
  6. Derksen, Katharina
  7. Demirci, Özlem
  8. Göçener, Defne
  9. AlWahsh, Mohammad
  10. Lambert, Jörg
  11. Lindskog, Cecilia
  12. Schmidt, Marcus
  13. Brenner, Walburgis
  14. Baumann, Matthias
  15. Zent, Eldar
  16. Zischinsky, Mia-Lisa
  17. Hellwig, Birte
  18. Madjar, Katrin
  19. Rahnenführer, Jörg
  20. Overbeck, Nina
  21. Reinders, Jörg
  22. Cadenas, Cristina ORCID logo
  23. Hengstler, Jan ORCID logo
  24. Edlund, Karolina ORCID logo
  25. Marchan, Rosemarie ORCID logo

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WeightNameValue
1000 Titel
  • Inhibiting the glycerophosphodiesterase EDI3 in ER-HER2+ breast cancer cells resistant to HER2-targeted therapy reduces viability and tumour growth
1000 Autor/in
  1. Keller, Magdalena |
  2. Rohlf, Katharina |
  3. Glotzbach, Annika |
  4. Leonhardt, Gregor |
  5. Lüke, Simon |
  6. Derksen, Katharina |
  7. Demirci, Özlem |
  8. Göçener, Defne |
  9. AlWahsh, Mohammad |
  10. Lambert, Jörg |
  11. Lindskog, Cecilia |
  12. Schmidt, Marcus |
  13. Brenner, Walburgis |
  14. Baumann, Matthias |
  15. Zent, Eldar |
  16. Zischinsky, Mia-Lisa |
  17. Hellwig, Birte |
  18. Madjar, Katrin |
  19. Rahnenführer, Jörg |
  20. Overbeck, Nina |
  21. Reinders, Jörg |
  22. Cadenas, Cristina |
  23. Hengstler, Jan |
  24. Edlund, Karolina |
  25. Marchan, Rosemarie |
1000 Erscheinungsjahr 2023
1000 LeibnizOpen
1000 Publikationstyp
  1. Artikel |
1000 Online veröffentlicht
  • 2023-01-20
1000 Erschienen in
1000 Quellenangabe
  • 42(1):25
1000 FRL-Sammlung
1000 Copyrightjahr
  • 2023
1000 Lizenz
1000 Verlagsversion
  • https://doi.org/10.1186/s13046-022-02578-w |
  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9854078/ |
1000 Ergänzendes Material
  • https://jeccr.biomedcentral.com/articles/10.1186/s13046-022-02578-w#Sec24 |
1000 Publikationsstatus
1000 Begutachtungsstatus
1000 Sprache der Publikation
1000 Abstract/Summary
  • BACKGROUND: Intrinsic 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. METHODS: EDI3 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. RESULTS: In 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. CONCLUSIONS: Our 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.
1000 Sacherschließung
lokal GPCPD1
lokal breast cancer
lokal choline metabolism
lokal HER2 positive breast cancer
lokal HER2‐targeting therapy resistance
1000 Fächerklassifikation (DDC)
1000 Liste der Beteiligten
  1. https://frl.publisso.de/adhoc/uri/S2VsbGVyLCBNYWdkYWxlbmE=|https://frl.publisso.de/adhoc/uri/Um9obGYsIEthdGhhcmluYQ==|https://orcid.org/0009-0001-1678-794X|https://orcid.org/0000-0002-9261-7539|https://frl.publisso.de/adhoc/uri/TMO8a2UsIFNpbW9u|https://frl.publisso.de/adhoc/uri/RGVya3NlbiwgS2F0aGFyaW5h|https://frl.publisso.de/adhoc/uri/RGVtaXJjaSwgw5Z6bGVt|https://frl.publisso.de/adhoc/uri/R8O2w6dlbmVyLCBEZWZuZQ==|https://frl.publisso.de/adhoc/uri/QWxXYWhzaCwgTW9oYW1tYWQ=|https://frl.publisso.de/adhoc/uri/TGFtYmVydCwgSsO2cmc=|https://frl.publisso.de/adhoc/uri/TGluZHNrb2csIENlY2lsaWE=|https://frl.publisso.de/adhoc/uri/U2NobWlkdCwgTWFyY3Vz|https://frl.publisso.de/adhoc/uri/QnJlbm5lciwgV2FsYnVyZ2lz|https://frl.publisso.de/adhoc/uri/QmF1bWFubiwgTWF0dGhpYXM=|https://frl.publisso.de/adhoc/uri/WmVudCwgRWxkYXI=|https://frl.publisso.de/adhoc/uri/WmlzY2hpbnNreSwgTWlhLUxpc2E=|https://frl.publisso.de/adhoc/uri/SGVsbHdpZywgQmlydGU=|https://frl.publisso.de/adhoc/uri/TWFkamFyLCBLYXRyaW4=|https://frl.publisso.de/adhoc/uri/UmFobmVuZsO8aHJlciwgSsO2cmc=|https://frl.publisso.de/adhoc/uri/T3ZlcmJlY2ssIE5pbmE=|https://frl.publisso.de/adhoc/uri/UmVpbmRlcnMsIErDtnJn|https://orcid.org/0000-0003-3374-6418|https://orcid.org/0000-0002-1427-5246|https://orcid.org/0000-0002-0276-2143|https://orcid.org/0000-0003-4414-1633
1000 Label
1000 Förderer
  1. Project DEAL |
  2. Deutsche Krebshilfe |
  3. Deutsche Forschungsgemeinschaft |
  4. Knut and Alice Wallenberg foundation |
1000 Fördernummer
  1. -
  2. 70114035
  3. HE2509/10
  4. -
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  2. -
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    1000 Förderprogramm -
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  2. 1000 joinedFunding-child
    1000 Förderer Deutsche Krebshilfe |
    1000 Förderprogramm -
    1000 Fördernummer 70114035
  3. 1000 joinedFunding-child
    1000 Förderer Deutsche Forschungsgemeinschaft |
    1000 Förderprogramm -
    1000 Fördernummer HE2509/10
  4. 1000 joinedFunding-child
    1000 Förderer Knut and Alice Wallenberg foundation |
    1000 Förderprogramm -
    1000 Fördernummer -
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1000 Erstellt am 2024-06-21T11:45:38.041+0200
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