Botanical estrogens are widely consumed by women with the expectation that they provide a safe, natural source of estrogens to replace the loss of endogenous estrogen in the menopause. Because estrogens can have diverse effects in target cells, including the stimulation of some breast cancers, this unregulated consumption of botanical estrogens might not contribute uniformly to healthy aging. Estrogens regulate gene transcriptional programs and the physiology of many reproductive and non-reproductive tissues, and the mechanisms by which they act are multi-faceted, involving two estrogen receptors, ERa and ER?, and nuclear-initiated and extra-nuclear-initiated, kinase-mediated pathways. With botanical estrogens, little is known about these mechanistic and cellular aspects. Our overall goal is to use a systems biology approach to provide a molecular and cellular profile of the activity of the botanical estrogens we will be studying, from soy, wild yam, licorice root, and dong quai, to enable determination of whether these botanical estrogens have activities similar to or distinct from estradiol or selective estrogen receptor modulators (SERMs).
In Aim 1, we will examine the molecular interactions of botanical estrogens with ERa and ER? by analysis of ligand binding, conformation and dynamics of the ligand-receptor complexes, and their interaction with key co-regulatory proteins.
In Aim 2, we will examine how the patterns of ER and protein kinase recruitment to chromatin binding sites (cistromes) and changes in gene expression (transcriptomes) in target cells are regulated by botanical estrogens through nuclear and extranuclear pathways on a genome-wide basis.
In Aim 3, we will generate mechanistic systems biology profiles that relate the cistromes, transcriptomes, and pathway-specific actions of botanical estrogens to their effects on cell functional properties. In this way, we will be able to place cell response to botanical estrogens on a firm mechanistic basis that will allow determination of whether botanical estrogens have similar or unique activities from those of other estrogens and provide fundamental information to inform future clinical studies. Our mechanistic and cellular findings will also be relevant in guiding and interpreting the work in other projects in this P50 program.
Little is known about the efficacy and safety of botanical estrogens that are being widely consumed by women for relief from menopausal symptoms. The botanical estrogen systems biology profiles generated through this project will provide crucial mechanistic information and a new conceptual framework for determining whether botanical estrogens have similar or unique activities from those of other estrogens.
|Kundu, Payel; Neese, Steven L; Bandara, Suren et al. (2018) The effects of the botanical estrogen, isoliquiritigenin on delayed spatial alternation. Neurotoxicol Teratol 66:55-62|
|Kundu, Payel; Korol, Donna L; Bandara, Suren et al. (2018) Licorice root components mimic estrogens in an object location task but not an object recognition task. Horm Behav 103:97-106|
|Dash, Michael B; Ajayi, Stephen; Folsom, Lynde et al. (2018) Spontaneous Infraslow Fluctuations Modulate Hippocampal EPSP-PS Coupling. eNeuro 5:|
|Korol, Donna L; Wang, Wei (2018) Using a memory systems lens to view the effects of estrogens on cognition: Implications for human health. Physiol Behav 187:67-78|
|Lu, Wenwen; Katzenellenbogen, Benita S (2017) Estrogen Receptor-? Modulation of the ER?-p53 Loop Regulating Gene Expression, Proliferation, and Apoptosis in Breast Cancer. Horm Cancer 8:230-242|
|Menazza, Sara; Sun, Junhui; Appachi, Swathi et al. (2017) Non-nuclear estrogen receptor alpha activation in endothelium reduces cardiac ischemia-reperfusion injury in mice. J Mol Cell Cardiol 107:41-51|
|Wang, Wendan; Belosay, Aashvini; Yang, Xujuan et al. (2016) Effects of letrozole on breast cancer micro-metastatic tumor growth in bone and lung in mice inoculated with murine 4T1 cells. Clin Exp Metastasis 33:475-85|
|Chambliss, Ken L; Barrera, Jose; Umetani, Michihisa et al. (2016) Nonnuclear Estrogen Receptor Activation Improves Hepatic Steatosis in Female Mice. Endocrinology 157:3731-3741|
|Boonmuen, Nittaya; Gong, Ping; Ali, Zulfiqar et al. (2016) Licorice root components in dietary supplements are selective estrogen receptor modulators with a spectrum of estrogenic and anti-estrogenic activities. Steroids 105:42-9|
|Weis, Karen E; Raetzman, Lori T (2016) Isoliquiritigenin exhibits anti-proliferative properties in the pituitary independent of estrogen receptor function. Toxicol Appl Pharmacol 313:204-214|
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