HIF-1 and HIF-2 also activate transcription of the ADAM12 gene, which encodes a protease that specifically clips the extracellular domain of heparin-bound EGF-like growth factor (HB-EGF), which binds to EGFR, leading to FAK phosphorylation; and ADAM12 knockdown in breast cancer cells is sufficient to block hypoxia-induced random motility, directed migration, and ECM invasion in vitro and metastasis from breast to lungs in vivo (86). Here, PTK2 is linked to breast cancer.