GIT1 protects against breast cancer growth through negative regulation of Notch

Songbai Zhang, Ayako Miyakawa, Malin Wickström, Cecilia Dyberg, Lauri Louhivuori, Manuel Varas-Godoy, Kati Kemppainen, Shigeaki Kanatani, Dagmara Kaczynska, Ivar Dehnisch Ellström, Lotta Elfman, Pauliina Kronqvist, Heli Repo, Katsuhiko Mikoshiba, Cecilia Sahlgren, John Inge Johnsen and Per Uhlén ()
Additional contact information
Songbai Zhang: Karolinska Institutet
Ayako Miyakawa: Karolinska Institutet
Malin Wickström: Karolinska Institutet
Cecilia Dyberg: Karolinska Institutet
Lauri Louhivuori: Karolinska Institutet
Manuel Varas-Godoy: Karolinska Institutet
Kati Kemppainen: Åbo Akademi University and University of Turku
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
Cecilia Sahlgren: Åbo Akademi University and University of Turku
John Inge Johnsen: Karolinska Institutet
Per Uhlén: Karolinska Institutet

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-28631-y

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