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Dual mechanisms of LYN kinase dysregulation drive aggressive behaviour in breast cancer cells

Tornillo, Giusy, Knowlson, Catherine, Kendrick, Howard, Cooke, Joe, Mirza, Hasan, Aurrekoetxea-Rodriguez, Iskander, d.M. Vivanco, Maria, Buckley, Niamh E., Grigoriadis, Anita and Smalley, Matthew J. 2018. Dual mechanisms of LYN kinase dysregulation drive aggressive behaviour in breast cancer cells. Cell Reports 25 (13) , pp. 3674-3692. 10.1016/j.celrep.2018.11.103

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Abstract

The SRC-family kinase LYN is highly expressed in triple-negative/basal-like breast cancer (TNBC) and in the cell of origin of these tumors, c-KIT-positive luminal progenitors. Here, we demonstrate LYN is a downstream effector of c-KIT in normal mammary cells and protective of apoptosis upon genotoxic stress. LYN activity is modulated by PIN1, a prolyl isomerase, and in BRCA1 mutant TNBC PIN1 upregulation activates LYN independently of c-KIT. Furthermore, the full-length LYN splice isoform (as opposed to the Δaa25–45 variant) drives migration and invasion of aggressive TNBC cells, while the ratio of splice variants is informative for breast cancer-specific survival across all breast cancers. Thus, dual mechanisms—uncoupling from upstream signals and splice isoform ratios—drive the activity of LYN in aggressive breast cancers.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
European Cancer Stem Cell Research Institute (ECSCRI)
Publisher: Elsevier
ISSN: 2211-1247
Funders: Cancer Research UK
Date of First Compliant Deposit: 21 November 2018
Date of Acceptance: 29 November 2018
Last Modified: 06 Apr 2020 17:00
URI: http://orca-mwe.cf.ac.uk/id/eprint/116972

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