Projects per year
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.
Original language | English |
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Article number | 1537 |
Journal | Nature Communications |
Volume | 13 |
Issue number | 1 |
DOIs | |
Publication status | Published - 1 Dec 2022 |
MoE publication type | A1 Journal article-refereed |
Keywords
- GIT1
- breast cancer
- Notch
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Notch counteracts replication stress to prevent cancer cell senescence
Cancer Foundation Finland, Sigrid Jusélius Foundation
01/05/20 → 31/12/23
Project: Foundation
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CellMech: Center of Excellence in Cellular Mechanostasis
Sahlgren, C., Sistonen, L., Eriksson, J., Toivola, D., Meinander, A., Cheng, F. & Jacquemet, G.
01/03/19 → 29/02/24
Project: Foundation
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AKT-mediated post-translational regulation of NOTCH3 – decoding the Notch phosphorylation switchboard for targeted therapies in cancer
01/09/19 → 30/09/22
Project: Foundation