Dual Mechanisms of LYN Kinase Dysregulation Drive Aggressive Behavior in Breast Cancer Cells

Giusy Tornillo; Catherine Knowlson; Howard Kendrick; Joe Cooke; Hasan Mirza; Iskander Aurrekoetxea-Rodríguez; Maria D M Vivanco; Niamh E Buckley; Anita Grigoriadis; Matthew J Smalley

doi:10.1016/j.celrep.2018.11.103

Dual Mechanisms of LYN Kinase Dysregulation Drive Aggressive Behavior in Breast Cancer Cells

Giusy Tornillo, Catherine Knowlson, Howard Kendrick, Joe Cooke, Hasan Mirza, Iskander Aurrekoetxea-Rodríguez, Maria D M Vivanco, Niamh E Buckley, Anita Grigoriadis, Matthew J Smalley

Health Sciences

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

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.

Original language	English
Pages (from-to)	3674-3692.e10
Number of pages	19
Journal	Cell reports
Volume	25
Issue number	13
DOIs	https://doi.org/10.1016/j.celrep.2018.11.103
Publication status	Published - 26 Dec 2018

Bibliographical note

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

Access to Document

10.1016/j.celrep.2018.11.103

Dual Mechanisms of LYN Kinase Dysregulation Drive Aggressive Behavior in Breast Cancer Cells
© 2018 The Author(s)
Final published version, 6.71 MBLicence: CC BY

https://pure.qub.ac.uk/en/publications/dual-mechanisms-of-lyn-kinase-dysregulation-drive-aggressive-beha

Cite this

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title = "Dual Mechanisms of LYN Kinase Dysregulation Drive Aggressive Behavior in Breast Cancer Cells",

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.",

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author = "Giusy Tornillo and Catherine Knowlson and Howard Kendrick and Joe Cooke and Hasan Mirza and Iskander Aurrekoetxea-Rodr{\'i}guez and Vivanco, {Maria D M} and Buckley, {Niamh E} and Anita Grigoriadis and Smalley, {Matthew J}",

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doi = "10.1016/j.celrep.2018.11.103",

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AU - Tornillo, Giusy

AU - Knowlson, Catherine

AU - Kendrick, Howard

AU - Cooke, Joe

AU - Mirza, Hasan

AU - Aurrekoetxea-Rodríguez, Iskander

AU - Vivanco, Maria D M

AU - Buckley, Niamh E

AU - Grigoriadis, Anita

AU - Smalley, Matthew J

PY - 2018/12/26

Y1 - 2018/12/26

N2 - 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.

AB - 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.

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KW - Adult

KW - Animals

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KW - Breast Neoplasms/enzymology

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KW - Female

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KW - Humans

KW - Isoenzymes/metabolism

KW - Mice

KW - NIMA-Interacting Peptidylprolyl Isomerase/metabolism

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KW - Proto-Oncogene Proteins c-kit/metabolism

KW - RNA Splicing/genetics

KW - Survival Analysis

KW - Up-Regulation

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