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LRIG1 regulates cadherin-dependent contact inhibition directing epithelial homeostasis and pre-invasive squamous cell carcinoma development.

Lu, L; Teixeira, VH; Yuan, Z; Graham, TA; Endesfelder, D; Kolluri, K; Al-Juffali, N; ... Janes, SM; + view all (2013) LRIG1 regulates cadherin-dependent contact inhibition directing epithelial homeostasis and pre-invasive squamous cell carcinoma development. J Pathol , 229 (4) 608 - 620. 10.1002/path.4148. Green open access

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Abstract

Epidermal growth factor receptor (EGFR) pathway activation is a frequent event in human carcinomas. Mutations in EGFR itself are, however, rare, and the mechanisms regulating EGFR activation remain elusive. Leucine-rich immunoglobulin repeats-1 (LRIG1), an inhibitor of EGFR activity, is one of four genes identified that predict patient survival across solid tumour types including breast, lung, melanoma, glioma, and bladder. We show that deletion of Lrig1 is sufficient to promote murine airway hyperplasia through loss of contact inhibition and that re-expression of LRIG1 in human lung cancer cells inhibits tumourigenesis. LRIG1 regulation of contact inhibition occurs via ternary complex formation with EGFR and E-cadherin with downstream modulation of EGFR activity. We find that LRIG1 LOH is frequent across cancers and its loss is an early event in the development of human squamous carcinomas. Our findings imply that the early stages of squamous carcinoma development are driven by a change in amplitude of EGFR signalling governed by the loss of contact inhibition.

Type: Article
Title: LRIG1 regulates cadherin-dependent contact inhibition directing epithelial homeostasis and pre-invasive squamous cell carcinoma development.
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1002/path.4148
Publisher version: http://dx.doi.org/10.1002/path.4148
Language: English
Additional information: © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Text made available to UCL Discovery by kind permission of Wiley. PMCID: PMC3806036
Keywords: Animals, Cadherins, Carcinoma, Squamous Cell, Cell Line, Tumor, Cell Proliferation, Cell Transformation, Neoplastic, Contact Inhibition, Gene Expression Regulation, Neoplastic, Homeostasis, Humans, Loss of Heterozygosity, Lung Neoplasms, Male, Membrane Glycoproteins, Mice, Mice, Inbred C57BL, Mice, Inbred NOD, Mice, Knockout, Mice, SCID, Multiprotein Complexes, Nerve Tissue Proteins, Precancerous Conditions, Receptor, Epidermal Growth Factor, Sequence Deletion, Signal Transduction
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Department of Education
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Respiratory Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci > Department of Targeted Intervention
URI: https://discovery.ucl.ac.uk/id/eprint/1380630
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