Nuclear co-localization and functional interaction of COX-2 and HIF-1 alpha characterize bone metastasis of human breast carcinoma

作者：Maroni Paola; Matteucci Emanuela; Luzzati Alessandro; Perrucchini Giuseppe; Bendinelli Paola; Desiderio Maria Alfonsina^*

来源：Breast Cancer Research and Treatment, 2011, 129(2): 433-450.

DOI：10.1007/s10549-010-1240-1

• Bone microenvironment
• Bone metastasis
• Breast cancer
• COX-2
• HIF-1

The aim of this article is to identify nuclear co-localization of COX-2 and HIF-1 alpha 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 metastatic clones, 1833 and MDA-231BO, and the parental MDA-MB231 cells, in vivo (1833-xenograft model), and in human-bone metastasis specimens. In 1833 cells in vitro, COX-2 signaling pathway was critical for nuclear HIF-1 alpha-protein expression/translocation, mechanisms determining HIF-1 activity and gene expression. The data were corroborated by immunohistochemistry in human-bone metastasis specimens. COX-2 and HIF-1 alpha showed wide co-localization in the nucleus, indicative of COX-2-nuclear import in transcriptionally activated metastatic cells and consistent with COX-2-HIF-1 alpha functional interaction. A network of microenvironmental signals controlled COX-2 induction and HIF-1 activation downstream. In fact, hypoxia through HGF and TGF-beta 1 autoregulatory loops triggered a specific array of transcription factors responsible for COX-2 transactivation. The novelty was that HGF and TGF-beta 1 biological signals were produced by hypoxic metastatic cells and, therefore, the microenvironment seemed to be modified by metastatic-cell engraftment in the bone. In agreement, HIF-1 alpha 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.

• 出版日期2011-9