Chief, Endocrinology, Diabetes, and Metabolism, Medicine
School of Medicine
Joint Appointment, Biological Chemistry
School of Medicine
Joint Appointment, Pharmacology
School of Medicine
M.D., Thomas Jefferson University and Medical College, 1975
Phone: (562) 826-5748
Fax: (562) 826-5515
|estrogen action in the cardiovascular system and in breast cancer|
|Division of Endocrinology/Medicine|
|Medicine Home Page|
|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.
|Publications||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 26: 2058-2070, 2012 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 32 (27): 3274-3285, 2013.
Pedram,A, Razandi, M, O’Mahony, F, Harvey, H, Harvey BJ, and Levin, ER. Estrogen reduces lipid content in the liver exclusively from membrane receptor signaling. Science Signaling 6,RA 36,2013.
Pedram,A, Razandi, M, Korach, K., Narayanan,R, Dalton,J, and Levin, ER. ERß selective agonist inhibits angiotensin-induced cardiovascular pathology in female mice. Endocrinology 154(11):4352-64 2013.
Cho, SK, Pedram, A, Levin, ER, Kwon, Y. Acid-degradable core-shell nanoparticles for reversed Tamoxifen-reistance in breast cancer by silencing manganese superoxide dismutase (MnSOD). Biomaterials 34(38):10228-10237, 2013
Pedram, A, Razandi, M, Narayanan, R, Dalton, J, McKinsey, A and Levin, ER. Estrogen regulates histone deacetylases to prevent cardiac hypertrophy. Mol Biol Cell In Press, 2013 and cover of journal.
|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
|Graduate Programs||Pharmacological Sciences|