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Vol. 17, Issue 5, 2125-2137, May 2006

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Functional Estrogen Receptors in the Mitochondria of Breast Cancer Cells

Ali Pedram ^* , Mahnaz Razandi ^* , Douglas C. Wallace  , and Ellis R. Levin ^*  ||

^* Division of Endocrinology, Veterans Affairs Medical Center, Long Beach, Long Beach, CA 90822; Department of Medicine, University of California, Irvine, Irvine CA 92717; Department of Biochemistry, University of California, Irvine, Irvine CA 92717; ^|| Department of Pharmacology, University of California, Irvine, Irvine CA 92717; and Department of the Center for Molecular and Mitochondrial Medicine and Genetics, University of California, Irvine, Irvine CA 92717

Submitted November 4, 2005; Revised January 26, 2006; Accepted February 15, 2006
Monitoring Editor: M. Bishr Omary

Steroid hormones have been reported to indirectly impact mitochondrial functions, attributed to nuclear receptor-induced production of proteins that localize in this cytoplasmic organelle. Here we show high-affinity estrogen receptors in the mitochondria of MCF-7 breast cancer cells and endothelial cells, compatible with classical estrogen receptors ER and ER. We report that in MCF-7, estrogen inhibits UV radiation-induced cytochrome C release, the decrease of the mitochondrial membrane potential, and apoptotic cell death. UV stimulated the formation of mitochondrial reactive oxygen species (mROS), and mROS were essential to inducing mitochondrial events of cell death. mROS mediated the UV activation of c-jun N-terminal kinase (JNK), and protein kinase C (PKC) , underlying the subsequent translocation of Bax to the mitochondria where oligomerization was promoted. E2 (estradiol) inhibited all these events, directly acting in mitochondria to inhibit mROS by rapidly up-regulating manganese superoxide dismutase activity. We implicate novel functions of ER in the mitochondria of breast cancer that lead to the survival of the tumor cells.

Abbreviations used: ER, estrogen receptor; ERK, extracellular-regulated protein kinase; JNK, c-Jun N-terminal kinase; MnSOD, manganese superoxide dismutase; PKC, protein kinase C; ROS, reactive oxygen species.

Address correspondence to: Ellis R. Levin (ellis.levin{at}med.va.gov).

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