Estrogens have the potential to afford atheroprotection, to prevent excess adiposity and its metabolic complications including insulin resistance, and to lessen hepatic steatosis. Cellular responses to estrogens occur through gene regulation by nuclear estrogen receptors (ER), and through signal initiation by plasma membrane-associated ER. Leveraging the potentially favorable cardiometabolic actions of estrogens has been challenging because their reproductive tract and cancer-promoting effects adversely impact the risk-benefit ratio of the therapy. In prior works we discovered that an estrogen dendrimer conjugate (EDC) comprised of ethinyl-estradiol (E2) molecules linked to a poly(amido)amine dendrimer selectively activates non-nuclear ER, and in mice EDC does not invoke a uterotrophic response or support ER-positive breast cancer growth. In the present investigation, we employed EDC to determine how selective non-nuclear ER activation impacts atherosclerosis, adiposity, glucose homeostasis and hepatic steatosis in female mice. In contrast to E2, EDC did not blunt atherosclerosis in hypercholesterolemic apoE-/- mice. Also in contrast to E2, EDC did not prevent the increase in adiposity caused by western diet feeding in wild-type mice, and it did not affect western diet-induced glucose intolerance. However, E2 and EDC had comparable favorable effect on diet-induced hepatic steatosis, and this was related to downregulation of fatty acid and triglyceride synthesis genes in the liver. Predictably only E2 caused a uterotrophic response. Thus, although non-nuclear ER activation does not prevent atherosclerosis or diet-induced obesity or glucose intolerance, it may provide a potential new strategy to combat hepatic steatosis without impacting the female reproductive tract or increasing cancer risk. Link
Monthly Archives: August 2016
Estrogen receptor-α and aryl hydrocarbon receptor involvement in the actions of botanical estrogens in target cells.
Botanical estrogen (BE) dietary supplements are consumed by women as substitutes for loss of endogenous estrogens at menopause. To examine the roles of estrogen receptor α (ERα) and aryl hydrocarbon receptor (AhR) and their crosstalk in the actions of BEs, we studied gene regulation and proliferation responses to four widely used BEs, genistein, daidzein, and S-equol from soy, and liquiritigen from licorice root in breast cancer and liver cells. BEs and estradiol (E2), acting through ERα, stimulated proliferation, ERα chromatin binding and target-gene expression. BEs but not E2, acting through AhR, bound to xenobiotic response element-containing chromatin sites and enhanced AhR target-gene expression (CYP1A1, CYP1B1). While E2 and TCDD acted quite selectively through their respective receptors, BEs acted via both receptors, with their AhR activity moderated by negative crosstalk through ERα. Both ERα and AhR should be considered as mediators of the biology and pharmacology of BEs. Link
ERα-XPO1 crosstalk controls tamoxifen sensitivity in tumors by altering ERK5 cellular localization
Most breast cancer deaths occur in women with recurrent, ERα (+), metastatic tumors. There is a critical need for therapeutic approaches that include novel, targetable mechanism-based strategies by which ERα (+) tumors can be resensitized to endocrine therapies. The objective of this study was to validate a group of nuclear transport genes as potential biomarkers to predict risk of endocrine therapy failure, and to evaluate the inhibition of XPO1, one of these genes as a novel means to enhance the effectiveness of endocrine therapies. Using advanced statistical methods, we found that expression levels of several of nuclear transport genes including XPO1 were associated with poor survival and predicted recurrence of tamoxifen-treated breast tumors in human breast cancer gene expression data sets. In mechanistic studies we showed that the expression of XPO1 determined the cellular localization of the key signalling proteins and the response to tamoxifen. We demonstrated that combined targeting of XPO1 and ERα in several tamoxifen resistant cell lines and tumor xenografts with XPO1 inhibitor, Selinexor (SXR) and tamoxifen restored tamoxifen sensitivity and prevented recurrence in vivo. The nuclear transport pathways have not previously been implicated in the development of endocrine resistance, and given the need for better strategies for selecting patients to receive endocrine modulatory reagents and improving therapy response of relapsed ERα(+) tumors, our findings show great promise for uncovering the role these pathways play in reducing cancer recurrences. Link
Estrogen and Microbiota Crosstalk: Should We Pay Attention?
Recent advances have suggested that steroid hormones such as estrogens, and gut microbiota might synergize to influence obesity, diabetes, and cancer. We discuss recent knowledge of the interactions between estrogens and gut microbiota, and new insights that might offer new approaches to influence this crosstalk and improve metabolic outcomes. Link