The cascade of caspase processing and activation is the core of apoptotic cell signaling. Initiator caspases are activated by adaptor-mediated clustering, which allows the intermolecular autoprocessing of the zymogens in close proximity. Caspase-8, the prototypical initiator critically involved in apoptosis induced by varied extrinsic stimuli, is physiologically recruited via a classical FasL/Fas/FADD pathway. Meanwhile, artificial models of caspase-8 activation have been proposed via inducible dimerization of a heterologous domain fused to the zymogen. Here, we describe the generation of a chimeric protein of caspase-8 and the ligand-binding domain (LBD) of estrogen receptor α (ERα), which dimerizes and undergoes autocleavage upon engagement by the ligand, estradiol. Breast cancer cells expressing this fusion protein exhibit apoptotic cell death in vitro and suppressed tumor growth in xenograft nude mice models in response to the administration of estrogen. Thus, the suicidal caspase-8/ERα-LBD protein, which reverses the mitogenic effects of estrogens, has potential to provide novel approaches to treating estrogen-dependent and -independent breast cancers.