Hypoxia-activated HIF-1α was also shown to induce the expression of collagen prolyl 4-hydroxylases (P4HA1 and P4HA2) and procollagen-lysine, 2-oxoglutarate 5-dioxygenases (PLOD2) in breast cancer-associated fibroblasts that promoted the ECM stiffness, where hydroxyproline-collagen expression was diminished in the fibroblast culture upon shRNA-knockdown of P4HA1 and P4HA2 (Seagroves et al., 2001). This evidence concerns the gene P4HA2 and breast carcinoma.