Apoptosis Estrogen Gets BAD

The steroid hormone estrogen has both pro- and antiapoptotic effects, depending on the cell type. In mammary tissue and breast cancer cell lines, the effect of estrogen 17-β-estradiol (E₂) in promoting cell survival has been attributed in part to regulating the expression of anti- and proapoptotic proteins Bcl-2 and Bak, respectively. Fernando and Wimalasena now report a nongenomic pathway by which E₂ blocks apoptosis in breast cancer (MCF7) cells. E₂ treatment reduced cell death in MCF7 cells that were exposed to proapoptotic stimuli including tumor necrosis factor-alpha (TNF-α). This protective effect of E₂ required the rapid phosphorylation and inactivation of BAD, a proapoptotic protein that forms a complex with Bcl-2 to destroy mitochondria integrity. BAD expression was not altered, which indicates that a nongenomic pathway is activated by E₂. When MCF7 cells were treated with TNF-α, phosphorylation of BAD on two serine residues decreased. However, E₂ treatment both restored BAD phosphorylation and inhibited the cell death response to TNF-α, which indicates a key role for BAD in apoptosis in this cellular context. Expression of a mutant form of BAD lacking the critical serine residues, or expression of antisense oligonucleotides to block the expression of endogenous BAD, reduced the apoptotic response to TNF-α. Expression of a dominant-negative form of Ras blocked E₂-mediated phosphorylation of BAD, which suggests that E2 acts through a Ras-dependent mechanism to affect BAD and cell survival. Pharmacologic inhibitors of either the phosphatidylinositol 3-kinase (PI3K)-Akt or the extracellular signal-regulated protein kinase (ERK)-Rsk1 signaling cascades indicated that BAD inactivation, in response to E_2, involved both Ras-controlled signaling pathways. The authors propose that the steroid hormone acts through both nongenomic signaling pathways as a mechanism to ensure cell survival when apoptotic stimuli are present simultaneously with estrogen.

R. I. Fernando, J. Wimalasena, Estradiol abrogates apoptosis in breast cancer cells through inactivation of BAD: Ras-dependent nongenomic pathways requiring signaling through ERK and Akt. Mol. Biol. Cell 15, 3266-3284 (2004). [Abstract] [Full Text]