ATF4 and glioblastoma: Finally, ATF4 expression in association with hypoxia-induced genes, such as adrenomedullin, is a biomarker of a poor prognosis for human breast cancer patients.137 Intratumoral hypoxia is one predominant feature of GBM and is associated with resistance to temozolomide (TMZ), the standard chemotherapy for GBM.138 TMZ sensitivity of both sensitive and resistant GBM cells is significantly enhanced under hyperoxia in vitro through the induction of caspase-dependent pathways.138 In addition, elevated PDIA1 expression also occurs in hypoxic brain tumor cells.