Ellis R. Levin
Professor and Vice-Chairman for Academic Affairs, Medicine
Chief, Endocrinology, Diabetes, and Metabolism, Medicine
Joint Appointment, Biological Chemistry
Joint Appointment, Pharmacology
|estrogen action in the cardiovascular system and in breast cancer|
|Division of Endocrinology/Medicine|
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|Biological Chemistry Home Page|
|Pharmacology Home Page|
Athalie Clarke UCI School of Medicine Research Award
Election into the Association of American Physicians
American Physiological Society 2013 Solomon A. Berson Award and Distinguished Lectureship in Endocrinology and Metabolism
My lab focuses on the plasma membrane estrogen receptor (ER) and its effects on the biology of estrogen action. This includes both in-vitro and in-vivo models. Our work always stems from a clinically important observation in humans that is mechanistically not understood. The focus currently is on 1) estrogen action to promote breast cancer development, and 2) the anti-hypertrophy effects of estrogen on the cardiomyocyte. As part of the studies, we are trying to understand the molecular structure /function aspects of the membrane estrogen receptor, that allows for signaling, and membrane localization. These studies involve mutagenesis or inhibition of endogenous receptors, and genetic mouse models (ER knockout).A focus on mitochondrial ER is also important in the lab, underlying tamoxifen sensitivity versus resistance in breast cancer.
Estrogen use after the menopause leads to increased risk of breast cancer. We have shown that this results from both increased proliferation of breast cancer cells and increased survival. In fact, tamoxifen, taxol or radiation treatment of breast cancer causes apoptosis, and we showed that estrogen prevents this. Both proliferation and survival effects of ER are importantly mediated through signaling to ERK MAP kinase via the membrane ER. This leads to detailed cell cycle events, and anti-apoptotic events that we have delineated. Important cell cyle events involving proliferation include estrogen-induced cyclins B and D1 proteins, and cdk4 and cdc2 activation. Signaling from the membrane ER requires cross-activation of the membrane EGF receptor, and we have published many of the details of this cross-talk between G-protein coupled ER and the tyrosine kinase EGFR. Our most recent work has defined the nature of the enzymes that plamitoylate ER and drive it to the plasma membrane.
We also recently found that estrogen protects cardiomyocytes against the development of hypertrophy, which fits with human studies showing protection by estrogen against the development of heart failure. The mechanisms and genes involved are being delineated using DNA array, siRNA and other approaches, in-vitro and in-vivo.
Pedram, A., Razandi, M., Aitkenhead, M, Hughes, CCW, and Levin, ER. Integration of the non-genomic and genomic actions of estrogen: membrane initiated signaling by steroid (MISS) to transcription and cell biology. J Biol Chem 277(52):50768-50775, 2002.
Razandi M, Pedram, A, Parks S, and Levin ER. Proximal events in ER signaling from the plasma membrane. J Biol Chem 278:2701-2712, 2003.
Levin, E.R. Bidirectional signaling between the estrogen receptor and the epidermal growth factor receptor. Mol Endocrinol 17: 309-317, 2003.
Razandi, M., Alton, G., Pedram, A., Ghonshani S., Webb D., and Levin, ER. Identification of a structural determinant for the membrane localization of ERalpha. Mol Cell Biol 23: 1633-1646, 2003.
Razandi M., Pedram, A, Rosen, E., and Levin, ER. BRCA1 inhibits membrane estrogen and growth factor receptor signaling to cell proliferation in breast cancer. Mol Cell Biol 24:5900-5913, 2004.
Guo, X., Razandi, M., Pedram, A., Kassab, G., and Levin, ER. Estrogen induces vascular wall dilation: Mediation through kinase signaling to nitric oxide and estrogen receptors alpha and beta. J Biol Chem, 280:19704-19710, 2005.
Levin, ER. Integration of the extra-nuclear and nuclear actions of estrogen. Mol Endocrinol 19(8): 1951-1959,2005.
Pedram, A., Razandi, R., Aitkenhead, M., and Levin, ER. 2005 Estrogen inhibits cardiomyocyte hypertrophy in-vitro: Antagonism of calcineurin-related hypertrophy through Induction of MCIP1. J Biol Chem 280:26339-26348,2005.
Kim JK., Pedram A., Razandi M., and Levin, ER. Estrogen prevents cardiomyocyte apoptosis through inhibition of reactive oxygen species and differential regulation of p38 isoforms. J Biol Chem 281:6760-6767,2006
Pedram, A., Razandi, M., Wallace, DC., and Levin, ER. Functional estrogen receptors in the mitochondria of breast cancer cells. Mol Biol Cell 17:2125-2137,2006.
Pedram, A., Razandi, M., and Levin, ER. Nature of functional estrogen receptors at the plasma membrane. Mol Endocrinol 20(9):1996-2009,2006.
Pedram, A., Razandi, M., Sainson, RCA., Kim,JK., Hughes, CC., and Levin, ER. A conserved mechanism for steroid receptor translocation to the plasma membrane. J Biol Chem 282:2278-2288, 2007.
Hammes, SR and Levin, ER. Extra-nuclear steroid receptors:Nature and function. Endo Rev 28(7):726-741,2007.
Levin, ER and Pietras RJ. Estrogen receptors outside the nucleus in breast cancer. Breast Cancer Research and Treatment 108:351-361,2008.
Pedram, A, Razandi, M, Kim, JK, O’Mahony, F, Lee, EYHP, Luderer, U, and Levin, ER. Developmental phenotype of a membrane only estrogen receptor alpha (MOER) mouse. J Biol Chem 284:3488-3495,2009.
Razandi, M, Pedram, A, Evinger, AJ, Kim, JK, Lee, EYHP and Levin, ER. Estrogen inhibits ATR signaling to cell cycle checkpoints and DNA repair Mol Biol Cell 20(14):3374-3389,2009.
Levin, ER. Plasma membrane estrogen receptors. Trends Endocrinology and Metabolism 20(10):477-82, 2009.
Razandi, M, Pedram, A, and Levin, ER. Heat shock protein 27 is required for sex steroid receptor trafficking to and functioning at the plasma membrane. Mol Cell Biol 30(13):3249-61, 2010.
Pedram, A, Razandi, M, O’Mahony, F, Lubahn, D, and Levin, ER. Estrogen receptor beta prevents cardiac fibrosis. Mol Endocrinol 24:2152-2165, 2010.
Levin, ER. Minireview: Extra-nuclear steroid receptors: Roles in modulation of cell functions. Mol Endocrinol 25:377-384, 2011.
Hammes, S and Levin, ER. Recent advances in Extra-nuclear steroid receptor actions. Endocrinology 152:4489-4495, 2011.
Levin, ER. Elusive extra-nuclear estrogen receptors in breast cancer. Clin Can Res, 18(1):6-8, 2012.
Pedram, A, Razandi M, Deschenes R, and Levin ER. DHHC 7 and 21 are palmitoylacyltranferases for sex steroid receptors. Mol Biol Cell, 23(1):188-199, 2012.
O’Mahony, F., Pedram, A., Razandi, M., Harvey, BH, and Levin ER. Estrogen modulates metabolic pathway adaptation to available glucose in breast cancer cells. Mol Endocrinology 2012 (In press) and cover of journal.
Razandi, M., Pedram, A., Jordan, VC, Fuqua, S, and Levin, ER. Tamoxifen regulates cell fate through mitochondrial estrogen receptor beta in breast cancer. Oncogene, 20 August 2012; doi: 10.1038/onc.2012.335.
|Grants||NCI 2009-2014 Extra-nuclear ER in breast cancer|
|VA 2010-2014 Estrogen prevents cardiac hypertrophy|
Association of American Physicians
American Society of Biochemistry and Molecular Biology
|Link to this profile||http://www.faculty.uci.edu/profile.cfm?faculty_id=3100|