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; Per Uhlén

doi:10.1038/s41467-022-28631-y

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, Per Uhlén^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Scientific › peer-review

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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
Article number	1537
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-28631-y
Publication status	Published - 22 Mar 2022
MoE publication type	A1 Journal article-refereed

Keywords

GIT1
breast cancer
Notch

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10.1038/s41467-022-28631-yLicence: CC BY

2022 GIT1 protects against breast cancer growth through negative regulation of NotchFinal published version, 4.91 MBLicence: CC BY

Notch counteracts replication stress to prevent cancer cell senescence
Sahlgren, C. (Principal Investigator)
Cancer Foundation Finland, Sigrid Jusélius Foundation
01/05/20 → 31/12/23
Project: Foundation
AKT-mediated post-translational regulation of NOTCH3 – decoding the Notch phosphorylation switchboard for targeted therapies in cancer
Sahlgren, C. (Principal Investigator)
01/09/19 → 30/09/22
Project: Foundation
CellMech: Center of Excellence in Cellular Mechanostasis
Sahlgren, C. (Principal Investigator), Sistonen, L. (Principal Investigator), Eriksson, J. (Principal Investigator), Toivola, D. (Principal Investigator), Meinander, A. (Principal Investigator), Cheng, F. (Principal Investigator) & Jacquemet, G. (Principal Investigator)
01/03/19 → 29/02/24
Project: Foundation

Cite this

Zhang, S., Miyakawa, A., Wickström, M., Dyberg, C., Louhivuori, L., Varas-godoy, M., Kemppainen, K., Kanatani, S., Kaczynska, D., Ellström, I. D., Elfman, L., Kronqvist, P., Repo, H., Mikoshiba, K., Sahlgren, C., Johnsen, J. I., & Uhlén, P. (2022). GIT1 protects against breast cancer growth through negative regulation of Notch. Nature Communications, 13(1), Article 1537. https://doi.org/10.1038/s41467-022-28631-y

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title = "GIT1 protects against breast cancer growth through negative regulation of Notch",

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.",

keywords = "GIT1, breast cancer, Notch",

author = "Songbai Zhang and Ayako Miyakawa and Malin Wickstr{\"o}m and Cecilia Dyberg and Lauri Louhivuori and Manuel Varas-godoy and Kati Kemppainen and Shigeaki Kanatani and Dagmara Kaczynska and Ellstr{\"o}m, {Ivar Dehnisch} and Lotta Elfman and Pauliina Kronqvist and Heli Repo and Katsuhiko Mikoshiba and Cecilia Sahlgren and Johnsen, {John Inge} and Per Uhl{\'e}n",

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month = mar,

day = "22",

doi = "10.1038/s41467-022-28631-y",

language = "English",

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journal = "Nature Communications",

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Zhang, S, Miyakawa, A, Wickström, M, Dyberg, C, Louhivuori, L, Varas-godoy, M, Kemppainen, K, Kanatani, S, Kaczynska, D, Ellström, ID, Elfman, L, Kronqvist, P, Repo, H, Mikoshiba, K, Sahlgren, C, Johnsen, JI & Uhlén, P 2022, 'GIT1 protects against breast cancer growth through negative regulation of Notch', Nature Communications, vol. 13, no. 1, 1537. https://doi.org/10.1038/s41467-022-28631-y

TY - JOUR

T1 - GIT1 protects against breast cancer growth through negative regulation of Notch

AU - Zhang, Songbai

AU - Miyakawa, Ayako

AU - Wickström, Malin

AU - Dyberg, Cecilia

AU - Louhivuori, Lauri

AU - Varas-godoy, Manuel

AU - Kemppainen, Kati

AU - Kanatani, Shigeaki

AU - Kaczynska, Dagmara

AU - Ellström, Ivar Dehnisch

AU - Elfman, Lotta

AU - Kronqvist, Pauliina

AU - Repo, Heli

AU - Mikoshiba, Katsuhiko

AU - Sahlgren, Cecilia

AU - Johnsen, John Inge

AU - Uhlén, Per

PY - 2022/3/22

Y1 - 2022/3/22

N2 - 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.

AB - 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.

KW - GIT1

KW - breast cancer

KW - Notch

U2 - 10.1038/s41467-022-28631-y

DO - 10.1038/s41467-022-28631-y

M3 - Article

SN - 2041-1723

VL - 13

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 1537

ER -

GIT1 protects against breast cancer growth through negative regulation of Notch

Abstract

Keywords

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Projects

Notch counteracts replication stress to prevent cancer cell senescence

AKT-mediated post-translational regulation of NOTCH3 – decoding the Notch phosphorylation switchboard for targeted therapies in cancer

CellMech: Center of Excellence in Cellular Mechanostasis

Cite this