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Mol. Biol. Cell 15 (7): 3266-3284

Copyright © 2004 by The American Society for Cell Biology.

Estradiol Abrogates Apoptosis in Breast Cancer Cells through Inactivation of BAD: Ras-dependent Nongenomic Pathways Requiring Signaling through ERK and Akt

Romaine Ingrid Fernando, and Jay Wimalasena *

Department of Obstetrics and Gynecology, and the Comparative and Experimental Medicine Program, Graduate School of Medicine, University of Tennessee, Knoxville, Tennessee 37920

Received for publication November 17, 2003. Revision received April 16, 2004. Accepted for publication April 18, 2004.

Monitoring Editor: Keith Yamamoto

Abstract: Estrogens such as 17-{beta} estradiol (E2) play a critical role in sporadic breast cancer progression and decrease apoptosis in breast cancer cells. Our studies using estrogen receptor-positive MCF7 cells show that E2 abrogates apoptosis possibly through phosphorylation/inactivation of the proapoptotic protein BAD, which was rapidly phosphorylated at S112 and S136. Inhibition of BAD protein expression with specific antisense oligonucleotides reduced the effectiveness of tumor necrosis factor-{alpha}, H2O2, and serum starvation in causing apoptosis. Furthermore, the ability of E2 to prevent tumor necrosis factor-{alpha}-induced apoptosis was blocked by overexpression of the BAD S112A/S136A mutant but not the wild-type BAD. BAD S112A/S136A, which lacks phosphorylation sites for p90RSK1 and Akt, was not phosphorylated in response to E2 in vitro. E2 treatment rapidly activated phosphatidylinositol 3-kinase (PI-3K)/Akt and p90RSK1 to an extent similar to insulin-like growth factor-1 treatment. In agreement with p90RSK1 activation, E2 also rapidly activated extracellular signal-regulated kinase, and this activity was down-regulated by chemical and biological inhibition of PI-3K suggestive of cross talk between signaling pathways responding to E2. Dominant negative Ras blocked E2-induced BAD phosphorylation and the Raf-activator RasV12T35S induced BAD phosphorylation as well as enhanced E2-induced phosphorylation at S112. Chemical inhibition of PI-3K and mitogen-activated protein kinase kinase 1 inhibited E2-induced BAD phosphorylation at S112 and S136 and expression of dominant negative Ras-induced apoptosis in proliferating cells. Together, these data demonstrate a new nongenomic mechanism by which E2 prevents apoptosis.


Article published online ahead of print. Mol. Biol. Cell 10.1091/mbc.E03-11-0823. Article and publication date are available at www.molbiolcell.org/cgi/doi/10.1091/mbc.E03-11-0823.

Abbreviations used: Dm, double mutant; DN, dominant negative; Wt, wild type.


Online version of this article contains supporting material. Online version is available at www.molbiolcell.org.

* Corresponding author. E-mail address: jwimalas{at}utk.edu.


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