Endocrine Therapies
David E. Thurston, Ilona Pysz in Chemistry and Pharmacology of Anticancer Drugs, 2021
Estrogen receptors are DNA-binding transcription factor proteins that represent the main class of the nuclear hormone family group of intracellular receptors and are activated by estrogen. Other members of the nuclear hormone family include the G protein-coupled receptor GPR30. The ERs are cytoplasmic receptors when not bound to estrogen, but labeling studies have shown that a fraction of the ERs reside permanently in the nucleus. Once estrogen has bound to the ER and activated it, the protein translocates into the nucleus and binds to a particular sequence of DNA (i.e., its recognition site) which regulates the activity of various genes. However, it has some additional functions independent of DNA binding (i.e., ligand-independent regulation – see below).
Estrogen Regulation of Cholangiocyte Proliferation
Gianfranco Alpini, Domenico Alvaro, Marco Marzioni, Gene LeSage, Nicholas LaRusso in The Pathophysiology of Biliary Epithelia, 2020
Estrogens are important inducers of growth and differentiation in target cells expressing estrogen receptors (ER).6 In the liver, ER are expressed in hepatocytes where estrogens regulate the process of growth and regeneration.6 After partial hepatectomy for example, the expression of ER in hepatocytes increases in association with their translocation to the nucleus where they induce DNA synthesis and favor the restoration of a normal liver mass.6–10 It is also known that estrogens are involved in the liver growth of neonates and that their chronic administration, for pharmacological purposes, in adults results in an enlargement of liver mass.6–10 Sex steroids may also influence the development and course of several liver diseases. Several studies, in fact, have addressed the relationship between ER expression, estrogen metabolism and biliary excretion and the development and course of chronic liver diseases.6–10
Biology of the endometrium
Barry G. Wren in Progress in the Management of the Menopause, 2020
Like ovarian estrogen and progesterone secretion, levels of receptors for estrogen and progesterone in the endometrium fluctuate markedly during the menstrual cycle. Both estrogen and progesterone receptor levels are higher in the proliferative phase and decline after ovulation10. Estrogen receptors are mainly located in epithelial cells, but occur also in stromal cells in proliferative phase endometrium. Progesterone receptors are most abundant around the time of ovulation, probably reflecting the ability of estrogen to increase progesterone receptors. Thereafter, they decrease in epithelial cells, but remain abundant in stromal cells also in the luteal phase of the menstrual cycle. The pattern of sex steroid receptors is maintained during the perimenopausal years. In addition, postmenopausal endometrium possesses ER and PR.
High serum concentration of estradiol may be a risk factor of prostate enlargement in aging male in China
Published in The Aging Male, 2020
Ding Xu, Yu Wu, Haibo Shen, Subo Qian, Jun Qi
In the estrogen pathway, estrogen receptors play an important role in modulating estrogen action. Estrogen action is mediated by two nuclear receptors: estrogen receptor-alpha (ERα) and estrogen receptor-beta (ERβ). ERα is a key mediator and putative therapeutic target for bladder complications of BPH. It has been reported that, while ERα is an oncogenic factor involved in cell proliferation and survival, ERβ is a protective factor that is anti-carcinogenic and pro-apoptotic. Recent experimental animal models on prostatic hyperplasia support estrogen receptors as critical factors in the prostatic hyperplastic response [29]. E2 has been shown to promote prostate proliferation through activating ERα [9] and cells expressing ERα were more prevalent in human BPH [30]. Moreover, Park et al. suggested that the mechanism of estrogen-regulated cell growth and the role of stromal cells may be different in normal versus BPH prostates. Normal stromal cells predominantly used rapid E2 signaling, but BPH stromal cells used classical ER-signaling, which was inhibited by treatment with ER antagonist [31]. To some extent, these may explain why the higher serum E2 level, the higher prostate volume in BPH patients.
Estrogen receptors as potential therapeutic target in endometrial cancer
Published in Journal of Receptors and Signal Transduction, 2023
Payel Guha, Koushik Sen, Piyali Chowdhury, Dilip Mukherjee
Estrogen receptors are of two types: ERα and ERβ and both share nearly identical DNA binding domains and more divergent ligand-binding domains with 60% homology [27]. In EC, ERα is expressed at much higher levels (2.9-fold) on average than estrogen receptor β [26]. In endometrium, estrogen can signal through ER in both genomic and nongenomic manner. In genomic signaling estrogen binds to nuclear estrogen receptor and regulate transcription, whereas in nongenomic action estrogen binds to the cell surface receptor and activates other signaling pathways (e.g. cAMP and MAPK) [28]. This nongenomic pathway allows more rapid responses than the genomic one. The molecular basis of ER having an oncogenic role in cancer has come from extensive research in breast cancer. Although estrogen signaling in both breast and EC share same phenotypic consequences, many aspects of ER differ in these two malignancies. A recent review [13] has cleared most of the unanswered questions. In this present review, we focus mainly on the molecular signaling of ERα and GPER-mediated EC.
Expression of programmed death-1 (PD-1) and its ligand PD-L1 is upregulated in endometriosis and promoted by 17beta-estradiol
Published in Gynecological Endocrinology, 2019
Lukanxuan Wu, Chunzi Lv, Yifeng Su, Chunyan Li, Hui Zhang, Xinbo Zhao, Mingjiang Li
Another important observation in this study is that E2 upregulated PD-L1 in eutopic endometrial epithelial cells in EM. To the best of our knowledge, this study is the first to demonstrate this effect of E2 on the PD-L1 expression on endometrial cells. Shen et al. reported that the expression of PD-L1 is susceptible to direct E2 regulation in the female reproductive tract [21]. In addition, a recent study has shown that E2 increases the expression of the PD-L1 protein by activating the phosphoinositide 3-kinase (PI3K)/Akt pathway in Ishikawa cells [27]. EM is an estrogen-dependent disease. E2 plays a vital role in inflammation and angiogenesis, and it promotes cell proliferation in EM [28,29]. Our previous study explored the 17β-estradiol-induced epithelial-mesenchymal transition in EM [30]. Thus, the current study suggests that E2 may be related to the immune dysfunctions in EM mediated by the PD-1/PD-L1 pathway. However, further studies including the expression of estrogen receptors and possible signaling involved are needed to explore the mechanism underlying the finding.
Related Knowledge Centers
- Estrogen
- Estrogen Receptor Alpha
- Estrogen Receptor Beta
- Nuclear Receptor
- Protein
- Receptor
- Estradiol
- Cell
- Hormone
- Membrane Estrogen Receptor