HIF-1 or HIF-2 function as heterodimeric proteins composed of the O 2-regulated HIF-1α or HIF-2α subunit, and a constitutively expressed HIF-1β subunit 14. Oxygen deprivation causes the stabilization of the hypoxia-inducible subunits (HIF-1α and HIF-2α) that regulate the cellular response to hypoxia 13. PO 2 values of <10 mmHg have been associated with an increased risk of metastasis and mortality 10, 11, 12. Data describing the pretreatment oxygenation status of solid tumors demonstrated that the mean partial pressure of oxygen ( PO 2) in breast tumors ranges from 2.5 to 28 mmHg, with a median value of 10 mmHg, as compared with 65 mmHg in normal human breast tissue 9. Hypoxia occurs in 90% of solids tumors due to limitations in diffusion and inefficient vasculature and has been identified as an adverse indicator for patient prognosis independent of clinical stage at diagnosis 7, 8. Pathologies, including cardiovascular disease, ischemia, fibrosis, and cancer, can be severely affected by hypoxia 5, 6. Hypoxia is an intensively investigated condition with profound effects on cell metabolism, migration, and angiogenesis during development and disease 1, 2, 3, 4.
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