Mechanism of Estrogen Receptor-alpha Action and the Consequence of Its Conditional Deletion on Mammary Gland Development and Function PDF Download
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Author: Yuxin Feng
Publisher:
ISBN:
Category :
Languages : en
Pages : 161
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Book Description
ERá is a critical regulator in breast cancer and mammary gland development. Deregulation of ER signaling correlates with abnormal mammary gland development and breast cancer. However, the role of epithelial ER remains to be clarified in vivo and the mechanism of ER signaling regulation is far from comprehensive. We hypothesize that 1) mammary epithelial ER plays critical roles in mammary gland development during pregnancy and lactation and that 2) novel, as yet identified factors in ER transcriptional regulation are involved in breast cancer development. The loxP-Cre system was used to generate epithelial ERKO mice. The well characterized MMTV-Cre and WAP-Cre transgenic mice were used to delete ER in mammary epithelial cells at different developmental stages. Early expression of MMTV-Cre arrested mammary gland development at the neonatal stage. Successive pregnancy and lactation activated epithelial ER ablation, which compromised side-branching, alveolar development, and epithelial proliferation. Further analysis revealed a massive loss of luminal epithelial cells presumably caused by apoptosis. The abnormal mammary gland development decreased milk production, thereby, caused growth retardation in the offspring. Similar phenotypes were also observed in MMTV-ERKO females in lactation. Thus, we concluded that epithelial ER is essential for mammary gland development during pregnancy and lactation stages. To further pursue the molecular mechanism of ER signaling regulation, a human mammary gland cDNA library was screened to identify novel factors that interact with ER. One novel ERá binding protein identified in the screen contains two conserved LXXLL motifs (NR-box) and a coiled-coil domain. The protein product, which we named NRCC, consists of 3 isoforms that vary in their N-terminal region. NRCC is conserved in vertebrates and its mRNA was detected in human breast cancer cells and mouse breast tumors. We found that NRCC-A interacts with ERá and enhances ERá transcriptional activity in human cancer cells. Moreover, NRCC-A co-localized with ERá in the cell nucleus and was recruited to ER target gene promoters. SiRNA analysis indicated that NRCC proteins are important for endogenous ERá-mediated transcriptional activity and estrogen dependent cell proliferation. Taken together, these data indicate that NRCC-A is a novel coactivator for ERá.
Author: Yuxin Feng
Publisher:
ISBN:
Category :
Languages : en
Pages : 161
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Book Description
ERá is a critical regulator in breast cancer and mammary gland development. Deregulation of ER signaling correlates with abnormal mammary gland development and breast cancer. However, the role of epithelial ER remains to be clarified in vivo and the mechanism of ER signaling regulation is far from comprehensive. We hypothesize that 1) mammary epithelial ER plays critical roles in mammary gland development during pregnancy and lactation and that 2) novel, as yet identified factors in ER transcriptional regulation are involved in breast cancer development. The loxP-Cre system was used to generate epithelial ERKO mice. The well characterized MMTV-Cre and WAP-Cre transgenic mice were used to delete ER in mammary epithelial cells at different developmental stages. Early expression of MMTV-Cre arrested mammary gland development at the neonatal stage. Successive pregnancy and lactation activated epithelial ER ablation, which compromised side-branching, alveolar development, and epithelial proliferation. Further analysis revealed a massive loss of luminal epithelial cells presumably caused by apoptosis. The abnormal mammary gland development decreased milk production, thereby, caused growth retardation in the offspring. Similar phenotypes were also observed in MMTV-ERKO females in lactation. Thus, we concluded that epithelial ER is essential for mammary gland development during pregnancy and lactation stages. To further pursue the molecular mechanism of ER signaling regulation, a human mammary gland cDNA library was screened to identify novel factors that interact with ER. One novel ERá binding protein identified in the screen contains two conserved LXXLL motifs (NR-box) and a coiled-coil domain. The protein product, which we named NRCC, consists of 3 isoforms that vary in their N-terminal region. NRCC is conserved in vertebrates and its mRNA was detected in human breast cancer cells and mouse breast tumors. We found that NRCC-A interacts with ERá and enhances ERá transcriptional activity in human cancer cells. Moreover, NRCC-A co-localized with ERá in the cell nucleus and was recruited to ER target gene promoters. SiRNA analysis indicated that NRCC proteins are important for endogenous ERá-mediated transcriptional activity and estrogen dependent cell proliferation. Taken together, these data indicate that NRCC-A is a novel coactivator for ERá.
Author: Kenneth S. Korach
Publisher: Springer Science & Business Media
ISBN: 9783540402503
Category : Medical
Languages : en
Pages : 240
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Book Description
From our current knowledge, it is obvious that estrogen action in volves more than reproduction and fertility. Rather, estrogens affect and influence a number of other organ systems such as the immune, cardiovascular and central nervous system as well as the gastrointes tinal tract, urinary tract and skeleton. The importance of estrogens and estrogen receptor activity is appreciated from the spectrum of significant physiological dysfunctions that occur when there is a loss The participants of the workshop VI Preface of the hormone or the receptor activity. Loss of estrogen, however (for instance during menopause), occurs with time and results in a variety of clinical conditions. We know that the developmental loss of estrogen, as seen in clinical cases of aromatase gene mutations and experimental models, has dramatic effects in both men and women alike. The evidence that these effects are mediated through the estrogen receptor(s) is based on similar but not always identical phenotypes as observed in experimental animal models of estrogen receptor mutations as well as the single clinical case of an estrogen receptor alpha mutant patient. Developing an understanding of the spectrum of estrogen in a variety of tissues related to the condition of estrogen loss is a major and highly active clinical as well as basic scientific research area. Following the discovery of a second estrogen receptor and possible receptor ligand-independent activity as well as the genomic and non genomic actions of estrogen, it is clear that the mechanisms of the effects of estrogen are multifaceted.
Author: Kenneth S. Korach
Publisher: Springer Science & Business Media
ISBN: 3540495487
Category : Medical
Languages : en
Pages : 193
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Book Description
Current molecular understanding of estrogen action has greatly profited from advances in molecular cell biology. These advances, and their implications for clinical use, were discussed by leading researchers from industry and academia during an international symposium held in Berlin, 1-3 March 2006 and are featured in this volume.
Author:
Publisher:
ISBN:
Category :
Languages : en
Pages : 0
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Book Description
Our previous results have shown that the basement membrane (BM) regulated the expression and function of estrogen receptor-alpha (ERa) in mouse mammary epithelial cells. New results shown here indicate that the presence of lactogenic hormones was required for the regulatory effect of BM on ERa levels. We present evidence that cell adhesion to the BM components collagen-IV, through alpha 2 and beta 1 integrin subunits and laminin-l, through alpha 2, alpha 6 and beta 1 subunits are the relevant interactions responsible for transducing the signal of the BM that increases ERa expression. On the other hand, BM- induced changes in cell proliferation and cell morphology were not involved. Thus, the changes observed in ER expression and estrogenic effect when mammary epithelial cells are removed from the gland and placed in culture could be due to the disruption of the tissue organization and, in particular, to the lack of cell-matrix interactions on tissue culture plastic. Our system model could be useful to better understand the mechanisms involved in the regulation of ER expression and function during mammary gland development and breast tumor progression.
Author: Fritz F. Parl
Publisher: IOS Press
ISBN: 9780967335544
Category : Breast
Languages : en
Pages : 280
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Book Description
Estrogens have been implicated to play a role in the development of breast cancer. The purpose of this book is to provide a comprehensive analysis of experimental, clinical and epidemiological evidence in support of the carcinogenicity of estrogens.
Author: Kenneth S. Korach
Publisher: Springer
ISBN: 9783662053874
Category : Medical
Languages : en
Pages : 214
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Book Description
From our current knowledge, it is obvious that estrogen action in volves more than reproduction and fertility. Rather, estrogens affect and influence a number of other organ systems such as the immune, cardiovascular and central nervous system as well as the gastrointes tinal tract, urinary tract and skeleton. The importance of estrogens and estrogen receptor activity is appreciated from the spectrum of significant physiological dysfunctions that occur when there is a loss The participants of the workshop VI Preface of the hormone or the receptor activity. Loss of estrogen, however (for instance during menopause), occurs with time and results in a variety of clinical conditions. We know that the developmental loss of estrogen, as seen in clinical cases of aromatase gene mutations and experimental models, has dramatic effects in both men and women alike. The evidence that these effects are mediated through the estrogen receptor(s) is based on similar but not always identical phenotypes as observed in experimental animal models of estrogen receptor mutations as well as the single clinical case of an estrogen receptor alpha mutant patient. Developing an understanding of the spectrum of estrogen in a variety of tissues related to the condition of estrogen loss is a major and highly active clinical as well as basic scientific research area. Following the discovery of a second estrogen receptor and possible receptor ligand-independent activity as well as the genomic and non genomic actions of estrogen, it is clear that the mechanisms of the effects of estrogen are multifaceted.
Author: Rory Desmond Spence
Publisher:
ISBN:
Category :
Languages : en
Pages : 106
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Book Description
Estrogen has well documented neuroprotective effects in a variety of clinical and experimental disorders of the central nervous system (CNS). The beneficial effects of estrogens in CNS disorders include mitigation of clinical symptoms as well as attenuation of histopathological signs of neurodegeneration and inflammation. The cellular mechanisms that underlie these CNS effects of estrogens are uncertain, because a number of different cell types express estrogen receptors in the peripheral immune system and CNS. Here, we investigated the potential roles of two endogenous CNS cell types in estrogen-mediated neuroprotection. We selectively deleted estrogen receptor alpha or estrogen receptor beta from either neurons or astrocytes using well-characterized Cre-loxP systems for conditional gene knockout in mice and studied the effects of these conditional gene deletions in a well-characterized model of adoptive experimental autoimmune encephalomyelitis (EAE). We found that the pronounced and significant neuroprotective effects of systemic treatment with ERbeta ligand on clinical function, CNS inflammation, and axonal loss during EAE were not completely prevented by conditional deletion of ERbeta from astrocytes or neurons. Interestingly, we found that the pronounced and significant neuroprotective effects of systemic treatment with ERalpha ligand on clinical function, CNS inflammation, and axonal loss during EAE were completely prevented by conditional deletion of ERalpha from astrocytes, whereas conditional deletion of ERalpha from neurons had no significant effect. Given the differential neuroprotective effects of ERalpha ligand treatment versus ERbeta ligand treatment on astrocytes, as well on T-cell and macrophage inflammation, we looked for molecules within astrocytes that were affected by signaling through ERalpha, but not ERbeta. We found that ERalpha ligand treatment, but not ERbeta ligand treatment, decreased expression of the chemokines CCL2 and CCL7 by astrocytes in EAE. Together our data show that neuroprotection in EAE mediated via ERbeta signaling does not require ERbeta on astrocytes or neurons, whereas neuroprotection in EAE mediated via ERalpha signaling requires ERalpha on astrocytes, and not neurons, and reduces astrocyte expression of chemokines that contribute to CNS inflammation. These findings reveal important cellular differences in the neuroprotective mechanisms of estrogen signaling through ERalpha and ERbeta in EAE.
Author: Kyuri Kim
Publisher:
ISBN:
Category :
Languages : en
Pages :
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Book Description
Estrogens are associated with the development and progression of breast cancer in addition to their role in normal reproductive physiology, and estrogen receptors (ER) mediate the actions of estrogen in target tissues by regulating the expression of numerous biologically important target genes. The progression of human breast cancer and the development of resistance to endocrine therapies are thought to be associated with ER phosphorylation. We generated multiple combinations of ER phospho-mutants, at residues serine 104, 106, 118, 167, 236, and 305, and examined their impact on receptor half-life, the agonist and antagonist balance of selective estrogen receptor modulators (SERMs) and selective estrogen receptor downregulators (SERDs), the regulation of ER transcriptional activity, and stimulation of cell proliferation in response to estradiol and SERMs/SERD. We showed that changes in ER affecting the phosphorylation status of the receptor greatly impact receptor function and differential SERM and SERD modulated cellular responses that could contribute to resistance to endocrine therapies in breast cancer. We also studied the regulation of microRNAs (miRNAs) by estradiol and growth factors through ER and extracellular signal-regulated kinase 2 (ERK2) in order to understand their physiological impact on breast cancer. We identified nine miRNA- encoding genes harboring overlapping ER and ERK2 binding sites close to their transcription start sites, which require ER and ERK2 for transcriptional induction as well as estradiol- mediated miRNA regulation. We then identified TP63, a target of miR-101, miR-190 and miR- 196a2, and showed that TP63 plays an important role in estradiol- or growth factor-mediated cellular response in breast cancer cells (MCF-7 and MDA-MB-231) by increasing tumor cell growth and in vitro invasion mainly controlled by miR-196a2 action. These results suggest a tumor-suppressive role of miR-196a2 in regulating TP63 expression and the aggressive behavior of breast cancers.
Author: Fatou Jallow
Publisher:
ISBN:
Category :
Languages : en
Pages : 175
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Book Description
Author: Daniela Alida Parodi
Publisher:
ISBN:
Category : Cytology
Languages : en
Pages : 268
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Book Description
Early life exposure to estrogens and estrogen like contaminants in the environment are thought to increase the risk of developing breast cancer due to the early onset of puberty in the exposed female. However, the results of this study show that in utero exposure to the metalloestrogen cadmium altered mammary gland development independent of its effect on puberty onset. In utero exposure to the metal resulted in an expansion of the mammary stem and/or progenitor cell population in the neonatal gland and an increase in branching, epithelial cells, and density in the prepubertal gland. Puberty onset resulted in a further expansion of the mammary stem/progenitor cell population and the overexpression of estrogen receptor-alpha that was due to an increase and altered response to estradiol of the transcripts derived from exons O and OT. These results suggest that in utero exposure to cadmium may increase the risk of developing breast cancer by increasing stem/progenitor cell population, density, and estrogen receptor-alpha expression in the mammary gland.
