title: Microenvironmental stimuli affect Endothelin-1 signaling responsible for invasiveness and osteomimicry of bone metastasis from breast cancer.
abstract: The present study was undertaken to clarify the function(s) of Endothelin-1 and its receptors ETAR and ETBR in osteolytic-bone metastasis from breast cancer, and their regulation by hepatocyte and transforming growth factors (HGF, TGF-β) and hypoxia. The aim was to evaluate the adaptability of bone metastasis to microenvironmental stimuli through Endothelin-1-mediated epithelial-mesenchymal transition (EMT), or the reverse process MET, and through osteomimicry possible key features for bone colonization. We compared low (MCF-7) and high (MDA-MB231) invasive-breast carcinoma cells, and 1833-bone metastatic clone, with human pair-matched primary breast-carcinomas and bone metastases. Parental MDA-MB231 and the derived 1833-clone responded oppositely to the stimuli. In 1833 cells, TGF-β and hypoxia increased Endothelin-1 release, altogether reducing invasiveness important for engraftment, while Endothelin-1 enhanced MDA-MB231 cell invasiveness. The Endothelin-1-autocrine loop contributed to the cooperation of intracellular-signaling pathways and extracellular stimuli triggering MET in 1833 cells, and EMT in MDA-MB231 cells. Only in 1833 cells, HGF negatively influenced transactivation and release of Endothelin-1, suggesting a temporal sequence of these stimuli with an initial role of HGF-triggered Wnt/β-catenin pathway in metastatization. Then, Endothelin-1/ETAR conferred MET and osteomimetic phenotypes, with Runt-related transcription factor 2 activation and metalloproteinase 9 expression, contributing to colonization and osteolysis. Findings with human pair-matched primary ductal carcinomas and bone metastases gave a translational significance to the molecular study. Endothelin-1, ETAR and ETBR correlated with the acquisition of malignant potential, because of high expression already in the in situ carcinoma. These molecular markers might be used as predictive index of aggressive behavior and invasive/metastatic phenotype.
authors.affiliation: Dipartimento di Scienze Biomediche per la Salute, Molecular Pathology Laboratory, Università degli Studi di Milano, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Bendinelli
authors.affiliation: Istituto Ortopedico Galeazzi, IRCCS, Milano, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Maroni
authors.affiliation: Dipartimento di Scienze Biomediche per la Salute, Molecular Pathology Laboratory, Università degli Studi di Milano, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Matteucci
authors.affiliation: Istituto Ortopedico Galeazzi, IRCCS, Milano, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Luzzati
authors.affiliation: Istituto Ortopedico Galeazzi, IRCCS, Milano, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Perrucchini
authors.affiliation: Dipartimento di Scienze Biomediche per la Salute, Molecular Pathology Laboratory, Università degli Studi di Milano, Italy. Electronic address: a.desiderio@unimi.it.
authors.forename: Maria Alfonsina
authors.initials: MA
authors.lastname: Desiderio
mesh_terms: D001859:Bone Neoplasms / Q000235:genetics* / Q000473:pathology / Q000556:secondary; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D019332:Endothelin-1 / Q000235:genetics* / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D009361:Neoplasm Invasiveness / Q000235:genetics; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism; D059016:Tumor Microenvironment; D060449:Wnt Signaling Pathway / Q000235:genetics
chemical_list: D019332:Endothelin-1; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D016212:Transforming Growth Factor beta
keywords: Bone metastasis; Endothelin-1 axis; Growth factors; Microenvironment; Osteomimicry