Studies on the roles of Bcl-2 and caspases in hormone-induced active cell death in estrogen receptor- and progesterone receptor-expressing breast cancer cells

Tamoxifen, an antiestrogen used to battle breast cancers that express estrogen receptors and progesterone receptors, induces growth arrest and active cell death in breast cancer cells. However, the clinical benefit of tamoxifen is limited by the emergence of tamoxifen resistance, increased risk of endometrial cancer, and cardiovascular complications. Therapies that target the progesterone receptor in combination with tamoxifen may provide an alternative approach for breast cancer treatment. Studies show that the antiprogestin mifepristone (MIF) enhances tamoxifen's efficacy in in vitro and in vivo models of breast cancer; however, the biochemical regulation of cell death in response to these hormonal therapies is not well characterized. The purpose of this research is to define the death-inducing actions of MIF, used as a monotherapy and in combination with tamoxifen, with a specific focus on the role of Bcl-2 and caspase activation in the death process. The data suggest (a) MIF effectively inhibits the growth of antiestrogen-resistant breast cancer cells, (b) MIF and tamoxifen elicit independent, caspase-mediated pathways of cell death, and (c) Bcl-2 appears to play a prominent role in regulating the growth inhibitory effects of MIF.; Index words. Breast cancer, Tamoxifen, Mifepristone, Bcl-2, Caspases, Active Cell Death.