TGFβ and Hypoxia Drive Breast Cancer Bone Metastases through Parallel Signaling Pathways in Tumor Cells and the Bone Microenvironment

Breast cancers frequently metastasize to bone, a site of hypoxia and high concentrations of active TGFβ, Skeletal metastases involve interactions between tumor and bone ceils driven by locally secreted proteins, many of which are increased by hypoxia and TGFβ. We asked whether these two factors promote bone metastases independently or synergistically. Of 16 prometastatic candidates, only VEGF and CXCR4 mRNA expression and promoter activity were additively increased by TGFβ and hypoxia. We tested interaction of HIFla and TGFβ pathways by HIF1α knockdown and TGFβ blockade with a dominant-negative type II receptor. Inhibition of either pathway in tumor cells decreased osteolytic lesion area and improved survival in a mouse model of bone metastases, with no additive effect when inhibiting both pathways. In contrast, combined inhibition of these pathways in both tumor and host cells using small molecule inhibitors,