estrogen action in the cardiovascular system and in breast cancer
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 (ERalpha selective cell pool 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. Recent work has focused on the pleuri-potent bone marrow-derived stem cell and how various cellular pools of ER collaborate to suppress commitment to adipogenesis.
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.
Hoa N, Ge L, Korach K, and Levin ER. Estrogen receptor beta maintains expression of KLF15 to prevent cardiac myocyte hypertrophy in female rodents. Mol Cell Endocrinol. 470:240-250, 2018
Allard C, Morford JJ, Xu B, Salwen B, Xu W, Desmoulins L, Zsombok A, Kim JK, Levin ER, Mauvais-Jarvis F.Loss of nuclear and membrane estrogen receptor-? differentially impairs insulin secretion and action in male and female mice. Diabetes 68(3):490-501, 2019
Hammes SR, Levin ER.Impact of estrogens in males and androgens in females. J Clin. Invest. 129(5):1818-1826, 2019 doi: 10.1172/JCI125755
Levin, ER and Hammes S. Nuclear receptors outside the nucleus: extranuclear signaling by steroid receptors. Nature Reviews Mol Cell Biol,17:783-797, 2016.
Levin ER. Editorial: Centenial Celebration-An interview with Dr Ellis Levin on 100 years of estrogens and health. Estrogen and the Cardiovascular System. Mol Endocrinol 30:155-157, 2016.
Maric-Bilkan C, Arnold AP, Taylor DA, Dwinell M, Howlett SE, Wenger N, Reckelhoff JF, Sandberg K, Churchill G Levin ER, Lundberg MS. Report of the National Heart, Lung, and Blood Institute Working Group on Sex Differences Research in Cardiovascular Disease: Scientific Questions and Challenges. Hypertension 67(5):802-807, 2016.
Nanjappa,M.K., Medrano TI, Hess, RA, Locker SH, Levin ER, and Cooke PS. Membrane-Localized Estrogen Receptor 1 Is Required for Normal Male Reproductive Development and Function in Mice. Endocrinology 157:2909-2919, 2016
Pedram A, Razandi M, Narayanan R, and Levin, ER. Estrogen Receptor Beta Signals to Inhibition of Cardiac Fibrosis. Mol Cell Endocrinology, 434:57-68, 2016.
Pedram A, Razandi M, Blumberg, B and Levin, ER Membrane and nuclear estrogen receptor alpha collaborate to suppress adipogenesis but not triglyceride content. FASEB J 30:230-240, 2016
Levin ER.Extra-nuclear steroid receptors are essential for steroid hormone actions. Annu Rev Med, 66:27.1-27.10, 2015.
Levin ER. Extra-nuclear estrogen receptors roles in physiology: Lessons from mouse models.2013 Solomon Berson Distinguished Researcher Award. American Journal of Physiology 307(2):E133-E140, 2014.
Pedram A, Razandi M, Lewis M, Hammes S, and Levin, ER. Membrane-localized estrogen receptor alpha is required for normal organ development and function. Developmental Cell 20(4):482-490, 2014
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.
Pedram, A, Razandi, M, Narayanan, R, Dalton, J, McKinsey, A and Levin, ER. Estrogen regulates histone deacetylases to prevent cardiac hypertrophy. Mol Biol, 2013 and cover of journal.
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
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.
Hammes, S and Levin, ER. Recent advances in Extra-nuclear steroid receptor actions. Endocrinology 152:4489-4495, 2011.
Levin, ER. Minireview: Extra-nuclear steroid receptors: Roles in modulation of cell functions. Mol Endocrinol 25:377-384, 2011.
Pedram, A, Razandi, M, O’Mahony, F, Lubahn, D, and Levin, ER. Estrogen receptor beta prevents cardiac fibrosis. Mol Endocrinol 24:2152-2165, 2010.
Extra-nuclear ER and nuclear ER in prostate development
(PI) Estrogen prevents cardiac hypertrophy
Association of American Physicians
American Society of Biochemistry and Molecular Biology