Importantly, although the contribution of the ER stress response UPR to tumorigenesis has been associated with its “adaptive” main feature, conferring to cancer cells the ability to cope with stress thus resulting in tumor growth, progression, and resistance to therapy, another “dark side” of UPR is emerging and relying on mutations occurring in the three sensor genes: ATF6, IRE1, and PERK, in cancers. This evidence concerns the gene ATF6 and neoplasm.