title: Hypoxia Selectively Enhances Integrin α5β1Receptor Expression in Breast Cancer to Promote Metastasis.
abstract: Metastasis is the leading cause of breast cancer mortality. Previous studies have implicated hypoxia-induced changes in the composition and stiffness of the extracellular matrix (ECM) in the metastatic process. Therefore, the contribution of potential ECM-binding receptors in this process was explored. Using a bioinformatics approach, the expression of all integrin receptor subunits, in two independent breast cancer patient datasets, were analyzed to determine whether integrin status correlates with a validated hypoxia-inducible gene signature. Subsequently, a large panel of breast cancer cell lines was used to validate that hypoxia induces the expression of integrins that bind to collagen (ITGA1, ITGA11, ITGB1) and fibronectin (ITGA5, ITGB1). Hypoxia-inducible factors (HIF-1 and HIF-2) are directly required for ITGA5 induction under hypoxic conditions, which leads to enhanced migration and invasion of single cells within a multicellular 3D tumor spheroid but did not affect migration in a 2D microenvironment. ITGB1 expression requires HIF-1α, but not HIF-2α, for hypoxic induction in breast cancer cells. ITGA5 (α5subunit) is required for metastasis to lymph nodes and lungs in breast cancer models, and high ITGA5 expression in clinical biopsies is associated with an increased risk of mortality.Implications:These results reveal that targeting ITGA5 using inhibitors that are currently under consideration in clinical trials may be beneficial for patients with hypoxic tumors.Mol Cancer Res; 15(6); 723-34. ©2017 AACR.
authors.affiliation: Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, Maryland.
authors.forename: Julia A
authors.initials: JA
authors.lastname: Ju
authors.affiliation: Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, Maryland.
authors.forename: Inês
authors.initials: I
authors.lastname: Godet
authors.affiliation: Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, Maryland.
authors.forename: I Chae
authors.initials: IC
authors.lastname: Ye
authors.affiliation: Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, Maryland.
authors.forename: Jungmin
authors.initials: J
authors.lastname: Byun
authors.affiliation: Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, Maryland.
authors.forename: Hasini
authors.initials: H
authors.lastname: Jayatilaka
authors.affiliation: Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland.|McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Sun Joo
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Lisha
authors.initials: L
authors.lastname: Xiang
authors.affiliation: Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland.|McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Debangshu
authors.initials: D
authors.lastname: Samanta
authors.affiliation: Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, Maryland.
authors.forename: Meng Horng
authors.initials: MH
authors.lastname: Lee
authors.affiliation: Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, Maryland.
authors.forename: Pei-Hsun
authors.initials: PH
authors.lastname: Wu
authors.affiliation: Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, Maryland.
authors.forename: Denis
authors.initials: D
authors.lastname: Wirtz
authors.affiliation: Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland.|Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland.|McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Gregg L
authors.initials: GL
authors.lastname: Semenza
authors.affiliation: Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland. dgilkes1@jhu.edu.|Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, Maryland.
authors.forename: Daniele M
authors.initials: DM
authors.lastname: Gilkes
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics; D039081:Integrin alpha5beta1 / Q000235:genetics* / Q000378:metabolism; D019012:Integrin beta1 / Q000235:genetics; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D011401:Promoter Regions, Genetic; D018874:Spheroids, Cellular / Q000473:pathology; D023041:Xenograft Model Antitumor Assays; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D039081:Integrin alpha5beta1; D019012:Integrin beta1; D000099162:Endothelial PAS Domain-Containing Protein 1