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The aim of the present paper was to identify nuclear co-localization of COX-2 and HIF-1α in human-bone metastasis of breast cancer, index of transcriptionally-activated cells and functional for gene expression. In particular, we verified whether hypoxia exerted a direct role on metastasis-gene expression or through COX-2 signaling, due to the relevance for clinical implications to individuate molecular targets for diagnosis and therapy. The experiments were performed in vitro with two autoregulatory loops triggered a specific array of transcription factors responsible for COX-2 transactivation. The novelty was that HGF and TGF-β1 biological signals were produced by hypoxic metastatic cells and, therefore, the microenvironment seemed to be modified by metastaticcell engraftment in the bone. In agreement, HIF-1α expression in bone-marrow supportive cells occurred in metastasis-bearing animals. Altogether, the data supported the pre-metastatic-niche theory. Our observations might be useful to design therapies against bone metastasis, by affecting the phenotype changes of metastatic cells occurring at the secondary growth site through COX-2-HIF-1 interaction.Keywords bone microenvironment · bone metastasis · breast cancer · COX-2 · HIF-1 3

3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1034-1042.