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GIT1 protects against breast cancer growth through negative regulation of Notch

Author

Listed:
  • Songbai Zhang

    (Karolinska Institutet)

  • Ayako Miyakawa

    (Karolinska Institutet
    Karolinska University Hospital)

  • Malin Wickström

    (Karolinska Institutet)

  • Cecilia Dyberg

    (Karolinska Institutet)

  • Lauri Louhivuori

    (Karolinska Institutet)

  • Manuel Varas-Godoy

    (Karolinska Institutet
    Universidad San Sebastián)

  • Kati Kemppainen

    (Åbo Akademi University and University of Turku
    Åbo Akademi University)

  • Shigeaki Kanatani

    (Karolinska Institutet)

  • Dagmara Kaczynska

    (Karolinska Institutet)

  • Ivar Dehnisch Ellström

    (Karolinska Institutet)

  • Lotta Elfman

    (Karolinska Institutet)

  • Pauliina Kronqvist

    (University of Turku)

  • Heli Repo

    (University of Turku)

  • Katsuhiko Mikoshiba

    (ShanghaiTech University
    RIKEN Center for Life Science Technologies (CLST)
    Toho University)

  • Cecilia Sahlgren

    (Åbo Akademi University and University of Turku
    Åbo Akademi University
    Eindhoven University of Technology)

  • John Inge Johnsen

    (Karolinska Institutet)

  • Per Uhlén

    (Karolinska Institutet)

Abstract

Hyperactive Notch signalling is frequently observed in breast cancer and correlates with poor prognosis. However, relatively few mutations in the core Notch signalling pathway have been identified in breast cancer, suggesting that as yet unknown mechanisms increase Notch activity. Here we show that increased expression levels of GIT1 correlate with high relapse-free survival in oestrogen receptor-negative (ER(-)) breast cancer patients and that GIT1 mediates negative regulation of Notch. GIT1 knockdown in ER(-) breast tumour cells increased signalling downstream of Notch and activity of aldehyde dehydrogenase, a predictor of poor clinical outcome. GIT1 interacts with the Notch intracellular domain (ICD) and influences signalling by inhibiting the cytoplasm-to-nucleus transport of the Notch ICD. In xenograft experiments, overexpression of GIT1 in ER(-) cells prevented or reduced Notch-driven tumour formation. These results identify GIT1 as a modulator of Notch signalling and a guardian against breast cancer growth.

Suggested Citation

  • Songbai Zhang & Ayako Miyakawa & Malin Wickström & Cecilia Dyberg & Lauri Louhivuori & Manuel Varas-Godoy & Kati Kemppainen & Shigeaki Kanatani & Dagmara Kaczynska & Ivar Dehnisch Ellström & Lotta Elf, 2022. "GIT1 protects against breast cancer growth through negative regulation of Notch," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28631-y
    DOI: 10.1038/s41467-022-28631-y
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    References listed on IDEAS

    as
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    2. Christina Curtis & Sohrab P. Shah & Suet-Feung Chin & Gulisa Turashvili & Oscar M. Rueda & Mark J. Dunning & Doug Speed & Andy G. Lynch & Shamith Samarajiwa & Yinyin Yuan & Stefan Gräf & Gavin Ha & Gh, 2012. "The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups," Nature, Nature, vol. 486(7403), pages 346-352, June.
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