Hypoxia-mediated translational activation of ITGB3 in breast cancer cells enhances TGF-β signaling and malignant features in vitro and in vivo
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Marta Sesé1,2,*, Pedro Fuentes1,2,*, Anna Esteve-Codina3, Eva Béjar1,2, Kimberley McGrail4, George Thomas5,6,7, Trond Aasen1,2 and Santiago Ramón y Cajal1,2
1Translational Molecular Pathology, Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain
2Spanish Biomedical Research Network Centre in Oncology, CIBERONC, Barcelona, Spain
3CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Universitat Pompeu Fabra, Barcelona, Spain
4Biomedical Research in Melanoma-Animal Models and Cancer Laboratory, Oncology Program, Vall d'Hebron Research Institute, VHIR-Vall d'Hebron Hospital, Barcelona-UAB, Barcelona, Spain
5Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati Medical School, Cincinnati, OH, USA
6Metabolism and Cancer Group, Molecular Mechanisms And Experimental Therapy In Oncology Program, Bellvitge Biomedical Research Institute, IDIBELL, Barcelona, Spain
7Physiological Sciences Department, Faculty of Medicine and Health Science, University of Barcelona, Barcelona, Spain
*These authors contributed equally to this work
Marta Sesé, email: [email protected]
Santiago Ramón y Cajal, email: [email protected]
Keywords: hypoxia; polysomes; breast cancer; migration; integrin beta 3
Received: July 05, 2017 Accepted: November 14, 2017 Published: December 12, 2017
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.
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