title: Hypoxia inducible factor-1 is activated by transcriptional co-activator with PDZ-binding motif (TAZ) versus WWdomain-containing oxidoreductase (WWOX) in hypoxic microenvironment of bone metastasis from breast cancer.
abstract: The hypoxic microenvironment of bone marrow favours the bone metastasis process. Hypoxia inducible factor (HIF)-1α is hallmark for hypoxia, correlating with poor prognosis and radio/chemotherapy resistance of primary-breast carcinoma. For bone metastasis, the molecular mechanisms involved in HIF-1α expression and HIF-1 (α/β heterodimer)-transcription factor activity are scarcely known. We studied the role played by HIF-1 in the cross-talk between neoplastic and supportive-microenvironmental cells. Also, WWdomain-containing oxidoreductase (Wwox) and transcriptional co-activator with PDZ-binding motif (TAZ) were taken into consideration evaluating whether these Hippo-pathway effectors affect bone-metastatic phenotype through HIF-1 activity. Considering bone-metastasis specimens, nuclear HIF-1α-TAZ co-localisation occurred in neoplastic and supportive cells, such as fibroblasts and endotheliocytes. Based on these data, the functional importance was verified using 1833-bone metastatic clone under hypoxia: nuclear HIF-1α and TAZ expression increased and co-immunoprecipitated, activating HIF-1-DNA binding and transactivation. In contrast, Wwox localised at perinuclear level in neoplastic cells of bone metastasis, being almost absent in supportive cells, and Wwox-protein expression diminished in hypoxic-1833 cells. Thus, TAZ regulation of HIF-1 activity might be important for bone-secondary growth, participating in metastasis-stroma cross-talk. Further, TAZ and HIF-1α-protein levels seemed correlated. In fact, blocking cyclooxygenase-2 with NS398 in hypoxic-1833 cells, not only HIF-1α decreased but also molecular-mechanism(s) upstream of the Hippo pathway were triggered: LATS-dependent TAZ phosphorylation seemed responsible for TAZ nucleus/cytoplasm translocation and degradation. In the 1833-xenograft model, NS398 largely prevented the outgrowth of bone-metastatic cells, probably related to remarkable-extracellular matrix assembly. We gained clinical insight into HIF-1α and TAZ as candidate biomarkers for bone avidity, relevant for early-therapeutic intervention against bone metastasis.
authors.affiliation: Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, 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, Università degli Studi di Milano, 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, Università degli Studi di Milano, Milano, Italy. Electronic address: a.desiderio@unimi.it.
authors.forename: Maria Alfonsina
authors.initials: MA
authors.lastname: Desiderio
mesh_terms: D000217:Acyltransferases; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000556:secondary*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015687:Cell Hypoxia / Q000235:genetics / Q000502:physiology*; D005260:Female; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D010088:Oxidoreductases / Q000378:metabolism*; D054731:PDZ Domains; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D059016:Tumor Microenvironment; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D000074584:WW Domain-Containing Oxidoreductase
chemical_list: D051793:Hypoxia-Inducible Factor 1; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D010088:Oxidoreductases; D000074584:WW Domain-Containing Oxidoreductase; C486071:WWOX protein, human; D000217:Acyltransferases; C108675:TAFAZZIN protein, human