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MBC in Press, published online ahead of print April 30, 2004
Mol. Biol. Cell 10.1091/mbc.E03-11-0823

A more recent version of this article appeared on July 1, 2004
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Submitted on November 17, 2003
Revised on April 16, 2004
Accepted on April 18, 2004

Estradiol abrogates apoptosis in breast cancer cells through inactivation of BAD: Ras dependent non-genomic pathways requiring signaling through ERK and Akt

Romaine Ingrid Fernando1 and Jay Wimalasena1*

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

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

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 ER-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 TNF-{alpha}, H2O2 and serum starvation in causing apoptosis. Furthermore, the ability of E2 to prevent TNF-{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 PI-3K/Akt and p90RSK1 to an extent similar to IGF-1 treatment. In agreement with p90RSK1 activation, E2 also rapidly activated ERK, 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 MEK1 inhibited E2 induced BAD phosphorylation at S112 and S136 and expression of DNRas induced apoptosis in proliferating cells. Together, this data demonstrate a new nongenomic mechanism by which E2 prevents apoptosis.




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