Tornillo, Giusy, Knowlson, Catherine orcid.org/0000-0001-5783-2690, Kendrick, Howard et al. (7 more authors) (2018) Dual Mechanisms of LYN Kinase Dysregulation Drive Aggressive Behavior in Breast Cancer Cells. Cell reports. 3674-3692.e10. ISSN 2211-1247
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved. |
Keywords: | Adolescent, Adult, Animals, BRCA1 Protein/deficiency, Breast Neoplasms/enzymology, Cell Line, Tumor, Cell Movement, Cell Proliferation, Epithelial Cells/metabolism, Female, Gene Expression Regulation, Neoplastic, HEK293 Cells, Humans, Isoenzymes/metabolism, Mice, NIMA-Interacting Peptidylprolyl Isomerase/metabolism, Neoplasm Invasiveness, Proto-Oncogene Proteins c-kit/metabolism, RNA Splicing/genetics, Survival Analysis, Up-Regulation, Young Adult, src-Family Kinases/genetics |
Dates: |
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Institution: | The University of York |
Academic Units: | The University of York > Faculty of Sciences (York) > Health Sciences (York) |
Depositing User: | Pure (York) |
Date Deposited: | 22 Apr 2020 09:30 |
Last Modified: | 27 Mar 2024 00:14 |
Published Version: | https://doi.org/10.1016/j.celrep.2018.11.103 |
Status: | Published |
Refereed: | Yes |
Identification Number: | https://doi.org/10.1016/j.celrep.2018.11.103 |
Related URLs: |
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Description: Dual Mechanisms of LYN Kinase Dysregulation Drive Aggressive Behavior in Breast Cancer Cells
Licence: CC-BY 2.5