ReviewRole of ERα36 in membrane-associated signaling by estrogen
Introduction
Estrogens regulate skeletal development and breast development in addition to regulating reproductive development [1]. These aforementioned functions are of particular interest as they are deleteriously affected by deficiency or abnormalities in estrogen signaling resulting in debilitating conditions, such as osteopenia or breast cancer progression [2], [3]. Estrogen normally regulates osteoblast and osteoclast function, thus abnormal estrogen levels following menopause may result in dysregulation of bone remodeling, leading to decreases in bone mineral retention, and ultimately causing osteopenia, a precursor to osteoporosis [4]. Causes of breast cancer are not as easily identified, but estrogen is a well-accepted as mediator of breast cancer progression. Moreover abnormal estrogen can promote progression of hormone-responsive cancers, such as uterine, ovarian, cervical and laryngeal [5], [6]. Therefore, the role of estrogen receptors in normal and abnormal physiological conditions is crucial to the understanding and treatment of these conditions.
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Steroid hormones and non-classical receptor signaling pathways
Estrogens belong to the class of biomolecules known as steroid hormones, which traditionally confer their effects through direct interaction with hormone-specific nuclear receptors. These include vitamin D3 metabolites such as 1α,25-dihydroxyvitamin-D3 (1α,25(OH)2D3) with the nuclear vitamin D3 receptor (VDR or nVDR), androgens such as testosterone and dihydrotestosterone (DHT) with androgen receptors (ARs), and estrogens, particularly 17β-estradiol (E2), with the estrogen receptors (ERs), ERα
Sexual dimorphism and estrogen receptors
As expected, presence of ERs and response to estradiol exhibit sexual dimorphism. Many studies on estrogen function and estrogen receptors are performed using breast cancer cells, which are typically from female cancers, and sexual dimorphism is not at issue. However, studies in non-cancerous tissues such as bone and cartilage illustrate the sexual dimorphism in physiological response to E2 [32]. What is surprising is that male cells still contain all the necessary signaling equipment necessary
Pathway cross-talk
Fig. 7 illustrates the various mechanisms by which ERs can mediate intracellular signaling. There remains an uncertainty as to an exclusive role of ERα36 as a membrane-associated receptor for E2. Studies on its role in breast and laryngeal cancer show that it works independently of traditional ERα, ERβ, and GPR30 [6], [34], [38]. It is clear that it can promote rapid signaling from the caveolae and from lipid rafts in the plasma membrane. Data also show that in non-cancerous tissue such as
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Osteoporosis in men: What is similar and what is different?
2020, Marcus and Feldman’s Osteoporosis24R,25-Dihydroxyvitamin D<inf>3</inf> regulates breast cancer cells in vitro and in vivo
2019, Biochimica et Biophysica Acta - General SubjectsOptimizing a recombinant estrogen receptor binding assay for analysis of herbal extracts
2019, Journal of Herbal MedicineEstradiol receptor profile and estrogen responsiveness in laryngeal cancer and clinical outcomes
2019, SteroidsCitation Excerpt :ERα36, which was found to be a key cellular and transcriptional regulator of proliferation and enhanced aggressiveness in breast cancer [13,16], was shown to reside in the plasma membrane of Hep2 cells and to mediate the activation of PKC in response to E2 via a mechanism comparable to that seen in the breast cancer cells [20]. ERα36 signaling had roles in tumorigenesis of laryngeal cancer enhancing proliferation and in the anti-apoptotic effect of E2 against chemotherapeutics such as Taxol [20]. In the present study we observed that the expression of ERs in laryngeal cancer cell lines is not uniform, which might explain the controversies in the literature regarding the presence and nature of the ER in laryngeal cancer.
Immunomodulation of carcinogens-induced steroids-dependent human diseases
2019, Saudi Journal of Biological SciencesCitation Excerpt :Also immunization against estradiol (Es) induced the regression of estrogen-sensitive tumors in mice (Caldwell et al., 1971). Abs specific to Es and progesterone (Pg) receptors (ER and PR) were able to modulate the rapid non-genomic effects of these hormones as agonists or antagonists on the various cells in vitro (Sömjen et al., 1997; Norfleet et al., 2000; Luconi et al., 2004; Modi et al., 2007; Chaudhri et al., 2012, 2014). Anti-idiotypic monoclonal Abs2 to Es acted as agonist of Es in the some in vitro systems while F(ab)2 dimer acted as agonist (Sömjen et al., 1996) presumably through membrane ER.