Mechanisms of tamoxifen-induced apoptosis

Tamoxifen (TAM) has been used in the treatment of breast cancer for over a decade. The observed clinical efficacy of TAM has been attributed to both g rowth arrest and induction of apoptosis within the breast cancer cells. Alt hough the primary mechanism of action of TAM is believed to be through the inhibition of estrogen receptor (ER), research over the years has indicated that additional, non-ER-mediated mechanisms exist. These include modulatio n of signaling proteins such as protein kinase C (PKC), calmodulin, transfo rming growth factor-beta (TGF beta), and the protooncogene c-myc. Recent st udies, including those from our laboratory, have implicated the role of cas pases and mitogen-activated protein kinases (MAPK), including c-Jun N-termi nal kinase (JNK) and p38 in TAM-induced apoptotic signaling. Oxidative stre ss, mitochondrial permeability transition (MPT), ceramide generation as wel l as changes in cell membrane fluidity may also play important roles in TAM -induced apoptosis. These various signaling pathways underlying TAM-induced apoptosis will be reviewed in this article.