title: A transcriptome-proteome integrated network identifies endoplasmic reticulum thiol oxidoreductase (ERp57) as a hub that mediates bone metastasis.
abstract: Bone metastasis is the most common distant relapse in breast cancer. The identification of key proteins involved in the osteotropic phenotype would represent a major step toward the development of new prognostic markers and therapeutic improvements. The aim of this study was to characterize functional phenotypes that favor bone metastasis in human breast cancer. We used the human breast cancer cell line MDA-MB-231 and its osteotropic BO2 subclone to identify crucial proteins in bone metastatic growth. We identified 31 proteins, 15 underexpressed and 16 overexpressed, in BO2 cells compared with parental cells. We employed a network-modeling approach in which these 31 candidate proteins were prioritized with respect to their potential in metastasis formation, based on the topology of the protein-protein interaction network and differential expression. The protein-protein interaction network provided a framework to study the functional relationships between biological molecules by attributing functions to genes whose functions had not been characterized. The combination of expression profiles and protein interactions revealed an endoplasmic reticulum-thiol oxidoreductase, ERp57, functioning as a hub that retained four down-regulated nodes involved in antigen presentation associated with the human major histocompatibility complex class I molecules, including HLA-A, HLA-B, HLA-E, and HLA-F. Further analysis of the interaction network revealed an inverse correlation between ERp57 and vimentin, which influences cytoskeleton reorganization. Moreover, knockdown of ERp57 in BO2 cells confirmed its bone organ-specific prometastatic role. Altogether, ERp57 appears as a multifunctional chaperone that can regulate diverse biological processes to maintain the homeostasis of breast cancer cells and promote the development of bone metastasis.
authors.affiliation: Biological Clues of the Invasive and Metastatic Phenotype Group, Bellvitge Biomedical Research Institute IDIBELL, L'Hospitalet de Llobregat, Barcelona E-08908, Spain.
authors.forename: Naiara
authors.initials: N
authors.lastname: Santana-Codina
authors.forename: Rafael
authors.initials: R
authors.lastname: Carretero
authors.forename: Rebeca
authors.initials: R
authors.lastname: Sanz-Pamplona
authors.forename: Teresa
authors.initials: T
authors.lastname: Cabrera
authors.forename: Emre
authors.initials: E
authors.lastname: Guney
authors.forename: Baldo
authors.initials: B
authors.lastname: Oliva
authors.forename: Philippe
authors.initials: P
authors.lastname: Clezardin
authors.forename: Omar E
authors.initials: OE
authors.lastname: Olarte
authors.forename: Pablo
authors.initials: P
authors.lastname: Loza-Alvarez
authors.forename: Andrés
authors.initials: A
authors.lastname: Méndez-Lucas
authors.forename: Jose Carlos
authors.initials: JC
authors.lastname: Perales
authors.forename: Angels
authors.initials: A
authors.lastname: Sierra
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000378:metabolism* / Q000556:secondary; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D019704:Protein Disulfide-Isomerases / Q000378:metabolism*; D025941:Protein Interaction Mapping; D020543:Proteome; D059467:Transcriptome; D014746:Vimentin / Q000378:metabolism
chemical_list: D015395:Histocompatibility Antigens Class I; D020543:Proteome; D014746:Vimentin; D019704:Protein Disulfide-Isomerases; C085868:PDIA3 protein, human