Hypoxia Signaling in Breast Tumor Progression, Dissemination, and Dormancy in the Bone
Todd, Vera Mayhew
Hypoxia is a common feature in tumors and induces signaling that promotes tumor cell survival, invasion, and metastasis. Questions remain, however, about the role of HIF signaling in tumor cell dissemination to bone and dormancy within the bone, the most common site of metastasis. To address these gaps in knowledge we first sought to characterize the downstream effectors of leukemia inhibitory factor receptor (LIFR), a known hypoxia-regulated dormancy promoting factor. We identified a cluster of LIFR-regulated extracellular matrix-related genes and found that one of these factors, collagen type XIV alpha 1 chain (COL14A1), decreased breast cancer cell proliferation in vitro. Taken together, these data suggest that hypoxia induced LIFR downregulation may induce dormancy escape by altering the interaction of breast cancer cells with the surrounding matrix. Second, to better understand the contributions of hypoxia inducible factor 1 alpha (HIF1α), HIF2α, and general HIF pathway activation in metastasis to lung and bone, we employed a PyMT-driven spontaneous murine mammary carcinoma model with mammary specific deletion of Hif1α, Hif2α, or von Hippel-Lindau factor (Vhl) using the Cre-lox system. We found that Hif1α or Hif2α deletion in the primary tumor decreased metastatic tumor burden in the bone marrow, while Vhl deletion increased bone tumor burden, supporting our hypothesis that active HIF signaling in breast tumor cells promotes their dissemination to the bone. Interestingly, Hif1α deletion increased metastatic tumor burden in the lung, while deletion of Hif2α or Vhl did not affect pulmonary metastasis, demonstrating that HIF signaling is capable of driving dissemination in a site-specific manner.