Hypoxia-mediated translational activation of ITGB3 in breast cancer cells enhances TGF-β signaling and malignant features in vitro and in vivo
Sesé, Marta (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Fuentes Varela, Pedro (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Esteve-Codina, Anna (Universitat Pompeu Fabra. Centre de Regulació Genòmica (CRG-UPF))
Bejar Serrano, Eva (Hospital Universitari Vall d'Hebron. Institut de Recerca)
McGrail, Kimberley (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Thomas, George (Universitat de Barcelona. Departament de Ciències Fisiològiques)
Aasen, Trond (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Ramón y Cajal, Santiago (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Universitat Autònoma de Barcelona

Data:	2017
Resum:	Breast cancer is the most prevalent malignancy in women and there is an urgent need for new therapeutic drugs targeting aggressive and metastatic subtypes, such as hormone-refractory triple-negative breast cancer (TNBC). Control of protein synthesis is vital to cell growth and tumour progression and permits increased resistance to therapy and cellular stress. Hypoxic cancer cells attain invasive and metastatic properties and chemotherapy resistance, but the regulation and role of protein synthesis in this setting is poorly understood. We performed a polysomal RNA-Seq screen in non-malignant breast epithelial (MCF10A) and TNBC (MDA-MB-231) cells exposed to normoxic or hypoxic conditions and/or treated with an mTOR pathway inhibitor. Analysis of both the transcriptome and the translatome identified mRNA transcripts translationally activated or repressed by hypoxia in an mTOR-dependent or -independent manner. Integrin beta 3 (ITGB3) was translationally activated in hypoxia and its knockdown increased apoptosis and reduced survival and migration, particularly under hypoxic conditions. Moreover, ITGB3 was required for sustained TGF-β pathway activation and for the induction of Snail and associated epithelial-mesenchymal transition markers. ITGB3 downregulation significantly reduced lung metastasis and improved overall survival in mice. Collectively, these data suggest that ITGB3 is translationally activated in hypoxia and regulates malignant features, including epithelial-mesenchymal transition and cell migration, through the TGF-β pathway, revealing a novel angle for the treatment of therapy-resistant hypoxic tumours.
Ajuts:	Instituto de Salud Carlos III PI13-00763 Instituto de Salud Carlos III PI16-00772 Instituto de Salud Carlos III CPII16-00042 Agència de Gestió d'Ajuts Universitaris i de Recerca 2014 SGR 1131
Nota:	Altres ajuts: The authors thank Antonio Gentilella for his excellent technical assistance. We also thank Anna Rosell, Ibane Abasolo, Yolanda Fernández and Joan Seoane for technical advice. We appreciate the helpful comments and suggestions of Ivan Topisirovic and Javier Hernández. This work was supported by Fondo de Investigaciones Sanitarias (PI14/01320), Redes Temáticas de Investigación Cooperativa en Salud (RD12/0036/0057) and CIBERONC (CB16/12/00363). TA acknowledges support from Instituto de Salud Carlos III grants PI13/00763, PI16/00772 and CPII16/00042, co-financed by the European Regional Development Fund (ERDF). SRC acknowledges support from the Generalitat de Catalunya (2014 SGR 1131). The CNAG-CRG laboratory is a member of the Spanish National Bioinformatics Institute (INB), PRB2-ISCIII and is supported by grant PT13/0001 of the PE I+D+i 2013-2016 funded by ISCIII and FEDER.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Hypoxia ; Polysomes ; Breast cancer ; Migration ; Integrin beta 3
Publicat a:	Oncotarget, Vol. 8 (december 2017) , p. 114856-114876, ISSN 1949-2553

DOI: 10.18632/oncotarget.23145
PMID: 29383126

21 p, 5.1 MB

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