Estrogen receptor signaling mechanisms

Abstract

The primary female sex hormones, estrogens, are responsible for the control of functions of the female reproductive system, as well as the development of secondary sexual characteristics that appear during puberty and sexual maturity. Estrogens exert their actions by binding to specific receptors, the estrogen receptors (ERs), which in turn activate transcriptional processes and/or signaling events that result in the control of gene expression. These actions can be mediated by direct binding of estrogen receptor complexes to specific sequences in gene promoters (genomic effects), or by mechanisms that do not involve direct binding to DNA (non-genomic effects). Whether acting via direct nuclear effects, indirect non-nuclear actions, or a combination of both, the effects of estrogens on gene expression are controlled by highly regulated complex mechanisms. In this chapter, we summarize the knowledge gained in the past 60 years since the discovery of the estrogen receptors on the mechanisms governing estrogen-mediated gene expression. We provide an overview of estrogen biosynthesis, and we describe the main mechanisms by which the female sex hormone controls gene transcription in different tissues and cell types. Specifically, we address the molecular events governing regulation of gene expression via the nuclear estrogen receptors (ERα, and ERβ) and the membrane estrogen receptor (GPER1). We also describe mechanisms of cross-talk between signaling cascades activated by both nuclear and membrane estrogen receptors. Finally, we discuss natural compounds that are able to target specific estrogen receptors and their implications for human health and medical therapeutics.

Role of Estrogen Receptors α and β in a Murine Model of Asthma: Exacerbated Airway Hyperresponsiveness and Remodeling in ERβ Knockout Mice

“…Asthma is characterized by inflammation and remodeling in the airways contributing to airway hyperresponsiveness (AHR) leading to episodic bronchoconstriction's (Holgate et al, 2009;Prakash, 2013;Prakash and Martin, 2014;Sathish et al, 2015b;Prakash, 2016). Epidemiological data suggests a role of sex in a variety of lung diseases, especially asthma (Riffo-Vasquez et al, 2007;Antunes et al, 2010;Bonds and Midoro-Horiuti, 2013;Lingappan et al, 2016;Wang et al, 2016;DeBoer et al, 2018;Fuentes and Silveyra, 2019a;Naeem and Silveyra, 2019).…”

“…Incidence of asthma is more common in pre-pubescent boys and adult women and the severity of asthma is increased during pregnancy (de Marco et al, 2000;Caracta, 2003;Carey et al, 2007b;Bonds and Midoro-Horiuti, 2013). In this context, multiple studies have explored and suggested a role for sex hormones in airway biology, especially estrogen (Keselman and Heller, 2015;Sathish et al, 2015a;Ambhore et al, 2018;Ambhore et al, 2019a;Ambhore et al, 2019b;Bhallamudi et al, 2019;Fuentes et al, 2019;Fuentes and Silveyra, 2019a). However, there is still a debate on the contradicting role of estrogen as few studies suggest its role in reducing inflammation (Myers and Sherman, 1994;Lieberman et al, 1995;Haggerty et al, 2003), while others suggest estrogen to induce AHR and inflammation (Riffo-Vasquez et al, 2007;Sakazaki et al, 2008).…”

“…Estrogen primarily acts through estrogen receptors (ER) ERa and ERb, which are widely considered to be nuclear receptors (Altucci and Gronemeyer, 2001). Multiple studies suggest both ERa and ERb signal through different cell signaling pathways eliciting different effects on cellular functions (Kuiper et al, 1996;Clarke et al, 2003;Heldring et al, 2007;Edvardsson et al, 2011;Williams and Lin, 2013;Aravamudan et al, 2017;Ambhore et al, 2018;Ambhore et al, 2019b;Bhallamudi et al, 2019;Fuentes and Silveyra, 2019a). ER's are expressed on a wide array of cells and our group has recently showed differential ER expression in human ASM cells, which is upregulated during inflammation/ asthma (especially ERb) (Aravamudan et al, 2017).…”

Lipid rafts as signaling hubs in cancer cell survival/death and invasion: implications in tumor progression and therapy

“…Approximately 70% of human breast cancers are hormone-dependent and estrogen receptor (ER)-positive (168). In mammals there are two ERs, ER (595 amino acids; 67 kDa) and ER (530 amino acids; 59 kDa), both members of the nuclear receptor superfamily of hormone-inducible transcription factors (169,170). Although most ERs localize in tumor cell nuclei, where they are translocated as dimers to induce transcriptional changes in estrogen-responsive genes, a significant pool of ERs occurs in extranuclear sites in tumor cells (171).…”

ERβ-induced MFN2 inhibits the migration and invasiveness of breast cancer cells by inhibiting the P-AKT signaling pathway

“…Many studies have confirmed that estrogen is involved in the development of human breast cancer (1,2). Since estrogen needs to bind to its receptors to function, an in-depth understanding of its two receptors, estrogen receptor α (ER α) and ER β, is essential to explore the pathogenesis of breast cancer (3). Currently, the medical community has a thorough understanding of the role of ER α in the development of breast cancer and uses this knowledge to guide the endocrine treatment of breast cancer.…”