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ARRDC3 suppresses breast cancer progression by negatively regulating integrin β4

Large-scale genetic analyses of human tumor samples have been used to identify novel oncogenes, tumor suppressors and prognostic factors, but the functions and molecular interactions of many individual genes have not been determined. In this study we examined the cellular effects and molecular mecha...

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Autores principales: Draheim, K M, Chen, H-B, Tao, Q, Moore, N, Roche, M, Lyle, S
Formato: Texto
Lenguaje:English
Publicado: Nature Publishing Group 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2997682/
https://www.ncbi.nlm.nih.gov/pubmed/20603614
http://dx.doi.org/10.1038/onc.2010.250
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author Draheim, K M
Chen, H-B
Tao, Q
Moore, N
Roche, M
Lyle, S
author_facet Draheim, K M
Chen, H-B
Tao, Q
Moore, N
Roche, M
Lyle, S
author_sort Draheim, K M
collection PubMed
description Large-scale genetic analyses of human tumor samples have been used to identify novel oncogenes, tumor suppressors and prognostic factors, but the functions and molecular interactions of many individual genes have not been determined. In this study we examined the cellular effects and molecular mechanism of the arrestin family member, ARRDC3, a gene preferentially lost in a subset of breast cancers. Oncomine data revealed that the expression of ARRDC3 decreases with tumor grade, metastases and recurrences. ARRDC3 overexpression represses cancer cell proliferation, migration, invasion, growth in soft agar and in vivo tumorigenicity, whereas downregulation of ARRCD3 has the opposite effects. Mechanistic studies showed that ARRDC3 functions in a novel regulatory pathway that controls the cell surface adhesion molecule, β-4 integrin (ITGβ4), a protein associated with aggressive tumor behavior. Our data indicates ARRDC3 directly binds to a phosphorylated form of ITGβ4 leading to its internalization, ubiquitination and ultimate degradation. The results identify the ARRCD3-ITGβ4 pathway as a new therapeutic target in breast cancer and show the importance of connecting genetic arrays with mechanistic studies in the search for new treatments.
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spelling pubmed-29976822010-12-17 ARRDC3 suppresses breast cancer progression by negatively regulating integrin β4 Draheim, K M Chen, H-B Tao, Q Moore, N Roche, M Lyle, S Oncogene Original Article Large-scale genetic analyses of human tumor samples have been used to identify novel oncogenes, tumor suppressors and prognostic factors, but the functions and molecular interactions of many individual genes have not been determined. In this study we examined the cellular effects and molecular mechanism of the arrestin family member, ARRDC3, a gene preferentially lost in a subset of breast cancers. Oncomine data revealed that the expression of ARRDC3 decreases with tumor grade, metastases and recurrences. ARRDC3 overexpression represses cancer cell proliferation, migration, invasion, growth in soft agar and in vivo tumorigenicity, whereas downregulation of ARRCD3 has the opposite effects. Mechanistic studies showed that ARRDC3 functions in a novel regulatory pathway that controls the cell surface adhesion molecule, β-4 integrin (ITGβ4), a protein associated with aggressive tumor behavior. Our data indicates ARRDC3 directly binds to a phosphorylated form of ITGβ4 leading to its internalization, ubiquitination and ultimate degradation. The results identify the ARRCD3-ITGβ4 pathway as a new therapeutic target in breast cancer and show the importance of connecting genetic arrays with mechanistic studies in the search for new treatments. Nature Publishing Group 2010-09-09 2010-07-05 /pmc/articles/PMC2997682/ /pubmed/20603614 http://dx.doi.org/10.1038/onc.2010.250 Text en Copyright © 2010 Macmillan Publishers Limited http://creativecommons.org/licenses/by-nc-sa/3.0/ This work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
spellingShingle Original Article
Draheim, K M
Chen, H-B
Tao, Q
Moore, N
Roche, M
Lyle, S
ARRDC3 suppresses breast cancer progression by negatively regulating integrin β4
title ARRDC3 suppresses breast cancer progression by negatively regulating integrin β4
title_full ARRDC3 suppresses breast cancer progression by negatively regulating integrin β4
title_fullStr ARRDC3 suppresses breast cancer progression by negatively regulating integrin β4
title_full_unstemmed ARRDC3 suppresses breast cancer progression by negatively regulating integrin β4
title_short ARRDC3 suppresses breast cancer progression by negatively regulating integrin β4
title_sort arrdc3 suppresses breast cancer progression by negatively regulating integrin β4
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2997682/
https://www.ncbi.nlm.nih.gov/pubmed/20603614
http://dx.doi.org/10.1038/onc.2010.250
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