Figure 2: A schematic diagram of the mechanisms underlying E2-induced apoptosis. (1) E2 activates nuclear ER to modulate multiple transcriptional factors including AP-1 complex [27]; (2) unfolded protein responsesare activated to reduce protein translation or increase protein degradation to reduce the burden of unfolded protein in the endoplasmic reticulum [22]; (3) failure to relieve endoplasmic reticulum stress induces apoptosis via crosstalk with mitochondria to increase reactive oxygen species (ROS) production or activate the mitochondrial pathway [22]; (4) the endoplasmic reticulum stress subsequently activates inflammation response and the extrinsic pathway of apoptosis [22,27]; (5) apoptosis can occur independent of the intrinsic and extrinsic pathways through activation of caspase 4, 12 [27].