Figure 1.

Endoplasmic reticulum (ER) stressors in cancer. Different factors/conditions related to cancer are considered ER stressors. The epidermal growth factor receptor family, composed of four members HER1, HER2, HER3, and HER4, is highly expressed in some cancers (for example, HER1/HER2 in gastric cancer and HER2 in breast cancer). The activation of HER2 and HER1 results in the activation of intracellular pathways including RAS/RAF/MEK/ERK, PI3K/AKT/TOR, Src family kinases, and STAT transcription factors that modulate survival, proliferation, mobility, and cancer cell invasiveness. Some tumors express RAS mutations that activate downstream signal transduction independently from upstream receptor activation. The increased cell proliferation relies on increased protein translation that is a source of ER stress in these tumors. On the same line, the lack of the activity of oncosuppressors such as p53 triggers uncontrolled cell proliferation and growth, which might induce ER stress. Extrinsic factors, i.e., independent from the genetic makeup of the tumor, as a low concentration of oxygen, hypoxia, might induce ER stress in tumors. Indeed, this is a common condition of solid tumors, which not only leads to the assembly of the two components HIF1alpha and HIF1beta of HIF1, rendering it an active transcription factor of genes involved in angiogenesis and cell proliferation, but also impairs the formation of post-translational disulfide bonds in proteins, triggering ER stress.