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Significance Previous work showed that primary tumors instigate systemic macroenvironmental changes supporting cancer progression and metastasis. Here, we show that activation of HIF signaling in osteoblast-lineage cells also generates systemic changes promoting breast cancer growth and dissemination in bones and outside the skeleton. Our results indicate that loss of bone homeostasis through alterations of the bone anabolism could affect breast cancer progression and present the skeleton as an important organ of the tumor macroenvironment. They also suggest that targeting the bone microenvironment could limit systemic tumor growth and dissemination in breast cancer.

HIF signaling in osteoblast-lineage cells promotes systemic breast cancer growth and metastasis in mice