A Transmembrane Intracellular Estrogen Receptor Mediates Rapid Cell Signaling

Rahman

The American Journal of Pathology

et al. 2011

We investigated the etiology and molecular mechanisms of bladder outlet obstruction (BOO). Transgenic (Tg) male mice overexpressing aromatase (Cyp19a1) under the ubiquitin C promoter in the estrogen-susceptible C57Bl/6J genetic background (AROM؉/ 6J) developed inguinal hernia by 2 months and severe BOO by 9 to 10 months, with 100% penetrance. These mice gradually developed uremia, renal failure, renal retention, and finally died. The BOO bladders were threefold larger than in age-matched wild-type (WT) males and were filled with urine on necropsy. Hypotrophic smooth muscle cells formed the thin detrusor urinae muscle, and collagen III accumulation contributed to the reduced compliance of the bladder. p-AKT and ER␣ expression were up-regulated and Pten expression was down-regulated in the BOO bladder urothelium. Expression of only ER␣ in the intradetrusor fibroblasts suggests a specific role of this estrogen receptor form in urothelial proliferation. Inactivation of Pten, which in turn activated the p-AKT pathway, was strictly related to the activation of the ER␣ pathway in the BOO bladders. Human relevance for these findings was provided by increased expression of p-AKT, PCNA, and ER␣ and decreased expression of PTEN in severe human BOO samples, compared with subnormal to mild samples. These findings clarify the involvement of estrogen excess and/or imbalance of the androgen/estrogen ratio in the molecular pathogenetic mechanisms of BOO and provide a novel lead into potential treatment strategies for BOO. A close interrelationship between lower urinary tract (bladder and urethra) symptoms, bladder outlet obstruction (BOO), and benign prostatic hyperplasia has been shown in aging men. 1-4 These symptoms, which include increased voiding frequency and urgency, nocturia, incomplete bladder emptying, hesitancy, weak stream, and straining, occur in mild to severe form in 50% to 85% of men over 50 years of age. 5-8 BOO, which reduces or prevents the flow of urine into the urethra, and urinary tract infection, bladder cancer, and incontinence comprise the major causes of lower urinary tract symptoms. 9,10 Congenital or acquired BOO can result in a stiff-walled, fibrotic bladder with low capacity, high pressure, and noncompliance, which may ultimately damage the kidneys. 10 The incidence of lower urinary tract symp-

Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Differential Gene Expression In Aromϩ/6j Male Bladder and Momentioning

confidence: 96%

See 1 more Smart Citation

Molecular Mechanisms of Bladder Outlet Obstruction in Transgenic Male Mice Overexpressing Aromatase (Cyp19a1)

Rahman

The American Journal of Pathology

et al. 2011

“…With a better understanding of hormone signaling the scenario has become more complex: the proliferative effect mediated by the interaction of ERα with the promoters of target genes is also influenced by membrane bound and cytosolic proteins that participate in triggering extra-nuclear signaling pathways. In addition, the proliferative signal could also be mediated by a member of the G-Protein Coupled Receptor (GPCR) superfamily, GPER [89-94] (see below). The large variety of estrogenic compounds corresponds to diverse affinities for the receptors.…”

Section: Effects Of Phyto- and Xenoestrogens On Human Breast Tissuementioning

confidence: 99%

“…Several studies have been conducted to identify the possible GPER ligands. Initially, binding with E2 was indicated with high specificity and an affinity constant Ki of about 6nM was measured by competition binding essays [94]. Later on, ER antagonists such as tamoxifen and ICI 182,780 were also shown to bind GPER [185], but in contrast to ER mediated effects, these molecules showed agonistic activities for GPER [89].…”

Section: Molecular Mechanismsmentioning

confidence: 99%

Combating Malaria with Plant Molecules: A Brief Update

Negi¹,

Gupta²,

Hamid

2013

CMC

Observations on the role of ovarian hormones in breast cancer growth, as well as interest in contraception, stimulated research into the biology of estrogens. The identification of the classical receptors ERα and ERβ and the transmembrane receptor GPER and the resolution of the structure of the ligand bound to its receptor established the principal molecular mechanisms of estrogen action. The presence of estrogen-like compounds in many plants used in traditional medicine or ingested as food ingredients, phytoestrogens, as well as the estrogenic activities of many industrial pollutants and pesticides, xenoestrogens, have prompted investigations into their role in human health. Phyto- and xenoestrogens bind to the estrogen receptors with a lower affinity than the endogenous estrogens and can compete or substitute the hormone. Xenoestrogens, which accumulate in the body throughout life, are believed to increase breast cancer risk, especially in cases of prenatal and prepuberal exposure whereas the role of phytoestrogens is still a matter of debate. At present, the application of phytoestrogens appears to be limited to the treatment of post-menopausal symptoms in women where the production of endogenous estrogens has ceased. In this review we discuss chemistry, structure and classification, estrogen signaling and the consequences of the interactions of estrogens, phytoestrogens and xenoestrogens with their receptors, the complex interactions of endogenous and exogenous ligands, the evaluation of the health risks related to xenoestrogens, and the perspectives toward the synthesis of potent third generation selective estrogen receptor modulators (SERMs).

Estrogen therapy induces an unfolded protein response to drive cell death in ER+ breast cancer

et al. 2019

Estrogens have been shown to elicit anticancer effects against estrogen receptor α ( ER )‐positive breast cancer. We sought to determine the mechanism underlying the therapeutic response. Response to 17β‐estradiol was assessed in ER + breast cancer models with resistance to estrogen deprivation: WHIM 16 patient‐derived xenografts, C7‐2‐ HI and C4‐ HI murine mammary adenocarcinomas, and long‐term estrogen‐deprived MCF ‐7 cells. As another means to reactivate ER , the anti‐estrogen fulvestrant was withdrawn from fulvestrant‐resistant MCF ‐7 cells. Transcriptional, growth, apoptosis, and molecular alterations in response to ER reactivation were measured. 17β‐estradiol treatment and fulvestrant withdrawal induced transcriptional activation of ER , and cells adapted to estrogen deprivation or fulvestrant were hypersensitive to 17β‐estradiol. ER transcriptional response was followed by an unfolded protein response and apoptosis. Such apoptosis was dependent upon the unfolded protein response, p53, and JNK signaling. Anticancer effects were most pronounced in models exhibiting genomic amplification of the gene encoding ER ( ESR 1 ), suggesting that engagement of ER at high levels is cytotoxic. These data indicate that long‐term adaptation to estrogen deprivation or ER inhibition alters sensitivity to ER reactivation. In such adapted cells, 17β‐estradiol treatment and anti‐estrogen withdrawal hyperactivate ER , which drives an unfolded protein response and subsequent growth inhibition and apoptosis. 17β‐estradiol treatment should be considered as a therapeutic option for anti‐estrogen‐resistant disease, particularly in patients with tumors harboring ESR 1 amplification or ER overexpression. Furthermore, therapeutic strategies that enhance an unfolded protein response may increase the therapeutic effects of ER reactivation.