Gender difference in the activity but not expression of estrogen receptors α and β in human lung adenocarcinoma cells

Dougherty, Susan; Mazhawidza, Williard; Bohn, Aimee R; Robinson, Krista A; Mattingly, Kathleen A.; Blankenship, Kristy A.; Huff, Mary O.; McGregor, W. Glenn; Klinge, Carolyn M.

doi:10.1677/erc.1.01118

Cited by 89 publications

(113 citation statements)

References 86 publications

(103 reference statements)

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“…Two breast cancer cell lines were selected as experimental controls. The MCF-7 cell line has been shown to express both ER isoforms (22,23), whereas T47D expresses ERa but not ERh (24). Total mRNA was extracted from all cell lines, and reverse transcription-PCR was performed to selectively amplify the gene of interest using primer pairs specific to either ERa or ERh.…”

Section: Resultsmentioning

confidence: 99%

The Estrogen Receptor Pathway in Rhabdomyosarcoma: A Role for Estrogen Receptor-β in Proliferation and Response to the Antiestrogen 4′OH-Tamoxifen

Greenberg

Sømme²,

Russnes³

et al. 2008

Cancer Research

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Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Highly malignant, RMS frequently fails to respond to conventional aggressive multimodal radiation, surgery, and chemotherapy treatment protocols that also cause significant sequelae in the growing child. Other tumors of mesenchymal origin, such as locally aggressive fibromatoses and desmoid tumors, have been successfully treated with a selective estrogen receptor (ER) modulator, tamoxifen. In an effort to identify new targets for RMS therapy, our group investigated the previously uncharacterized ER pathway in RMS cell culture and primary tumors. We detected ER isoform B (ERB), but not isoform A, RNA, and protein in five RMS cell lines. Immunohistochemical staining of primary RMS tumor sections confirmed high levels of ERB but not ERA protein.RMS cell growth was dramatically inhibited in steroid-free conditions, and this growth inhibition was rescued with 17-Bestradiol (E2) supplementation. Exposure of RMS cells to 4 ¶OH-tamoxifen (4OHT) decreased cell viability and inhibited colony formation as detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and colony-forming assays. 4OHT also induced apoptotic signaling in RMS cells as detected by cleavage of caspase-3 and poly(ADP)ribose polymerase. This effect increased 3-to 8-fold in steroid-deprived conditions but was rescued by supplementation with E2. Immunofluorescence studies detected a change in the subcellular localization of ERB in response to 4OHT. Together, these data suggest an active ERB-mediated signal transduction pathway in RMS. The ability of 4OHT to induce apoptotic signaling and disrupt estradiol-mediated proliferation provides a rationale to explore a role for selective ER modulators in the treatment of RMS. [Cancer Res 2008;68(9):3476-85]

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Section: Resultsmentioning

confidence: 99%

The Estrogen Receptor Pathway in Rhabdomyosarcoma: A Role for Estrogen Receptor-β in Proliferation and Response to the Antiestrogen 4′OH-Tamoxifen

Greenberg

Sømme²,

Russnes³

et al. 2008

Cancer Research

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“…Each trans-acting factor is encircled with a square. and sst2 (Halmos et al 2000, Campbell-Thompson et al 2001, Dougherty et al 2006, and in rodent central nervous system the arcuate nucleus expresses more sst2 in female than male (Shimizu et al 2005, Bouyer et al 2006. Since the expression of ERs is known to increase in progressed tumors (Deroo & Korach 2006), it is expected that the increased ER proteins may lead to induce the sst2 gene expression.…”

Section: Discussionmentioning

confidence: 99%

Identification of transcriptional regulatory elements in the human somatostatin receptor sst2 promoter and regions including estrogen response element half-site for estrogen activation

Kimura

Takamatsu²,

Yaoita

et al. 2007

Journal of Molecular Endocrinology

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The somatostatin receptor subtype 2 (sst2) mediates inhibition of hormone secretion and cell proliferation, and modulates neurotransmission. Its expression is widespread in various normal tissues and many malignant cells, and is up-regulated by estrogen in breast cancer cells. This study was undertaken to investigate molecular mechanism of transcriptional regulation of the human sst2 gene, for which an additional exon (exon 1) in the 5 0 -untranslated region was recently found.Transient transfection and mutational analysis showed that the immediate 5 0 -upstream region containing two Sp1(K54/K45 and K88/K79) and an ATF/CRE (K69/K62) sites provided full promoter activity. An EMSA together with transfection analysis in Sp1-deficient Drosophila Schneider line (SL2) cells showed that Sp1 acted on the proximal Sp1 site, whereas Sp3, Sp1, and Sp2 did on the distal Sp1 site. Activating transcription factor-2 (ATF)-2, c-Jun, and cyclic AMP response element-binding protein (CREB) interacted with the ATF/CRE site. Transcriptional activation by estrogen occurred through two different regions; one included these proximal elements and the other existed in the upstream region containing estrogen response element (ERE) half-site (K348/K344) and GC-rich sequence (K447/K414). This upstream estrogen responsiveness was observed in a human breast cancer T47D cell, but not in GH 3 or estrogen receptor a (ERa) -expressing HeLa cells, and was potentiated by overexpression of ERa or ERb, whose binding to the ERE half-site was verified by EMSAs. A chromatin immunoprecipitation assay suggested that ERa was recruited to the ERE half-site after estrogen treatment in T47D cells. The present results should provide a molecular basis for transcriptional regulation in a variety of physiological and pathological contexts of sst2-expressing tissues.

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“…Use of the classical ER antagonist ICI 182,780 on ERP expressing lung tumors reduced the proliferation ofNSCLC and this effect is proposed to be mediated through ERP (38). Recently, the analysis of ERa and ERP expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts revealed that E2 stimulated proliferation in lung cancer cells derived only from female patients (32). Lung adenocarcinoma cell lines derived from females were inhibited by 4-hydroxytamoxifen (4-0HT) and ICI 182,780 treatment, in agreement with previous studies.…”

Section: Additionally Lung Epithelial Cells and Lung Cancer Cells Exsupporting

confidence: 86%

“…Lung adenocarcinoma cell lines derived from females were inhibited by 4-hydroxytamoxifen (4-0HT) and ICI 182,780 treatment, in agreement with previous studies. In contrast, lung adenocarcinoma cell lines derived from male patients, although expressing equal amounts of ERa and ERP as those from females, were unresponsive to the effects ofE 2 , 4-0HT and ICI 182,780 (32).…”

Section: Additionally Lung Epithelial Cells and Lung Cancer Cells Exmentioning

confidence: 86%

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Regulation of nuclear respiratory factor-1 expression by 17beta-estradiol : a new mechanism for coordinating mitochondrial gene expression.

Mattingly¹,

AnnMarie²

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The mechanisms by which estrogens regulate mitochondrial activity are not completely understood. Chronic treatment of ovariectomized rats with estradiol (E 2 ) increased the amount of Nuclear Respiratory F actor-1 (NRF -1) protein in cerebral blood vessels. NRF-1 is a transcription factor that regulates the expression of nuclear-encoded mitochondrial genes including mitochondrial transcription factor A (TF AM), which, in tum, controls transcription of the mitochondrial genome. Here, I tested the hypothesis that E2 increases NRF -1 transcription through a genomic activation of estrogen receptor (ER) resulting in a coordinate increase in nuclear-and mitochondrial-encoded genes, mitochondrial respiratory activity, and mitochondrial biogenesis. E2 increased NRF-1 mRNA and protein in MCF-7 breast and H1793 lung adenocarcinoma cells in a time-, concentration-, and ER-dependent manner. E 2 -induced NRF-1 expression was inhibited by Actinomycin D, but not by inhibitors of the PI3K or MAPK pathways, indicating a genomic mechanism of E2 action. An estrogen response element in the NRF -1 promoter bound ERa and ERP in vitro and in chromatin immunoprecipitation assays in MCF-7 cells and activated reporter gene expression in transfected cells. The E 2 -induced increase in NRF-1 was followed in time by increased TFAM; Tfam-regulated, mtDNA-encoded lV CO! and ND!; and mitochondrial biogenesis. The selective ER modulators (SERMs) 4-hydroxytramoxifen (4-0HT) and raloxifene (RAL) also increased NRF-1 expression by a mechanism involving ER nongenomic and genomic activities. E 2 , 4-0HT, and RAL also increased NRF-1 expression in Human Umbilical Vein Endothelial Cells (HUVEC) by a genomic ER mechanism. Exposure to Diesel Exhaust Particle Extracts (DEPE) may promote vascular disease and DEPE are antagonists of genomic estrogen responses.DEPE suppressed the basal expression ofNRF-1 in HUVEC and ablated the stimulatory effect ofE 2 , 4-0HT, and RAL on NRF-1 transcription. Lastly, a known cardioprotective phytoestrogen, resveratrol, stimulated NRF -1 expression in HUVEC and inhibited the ability ofDEPE to suppress basal NRF-l. In summary, the research presented here characterizes a possibly important ER-mediated pathway to account for the observed beneficial effects of E2 on mitochondrial function. These results suggest that administration of E2 or SERMs may be beneficial in treating pathological conditions involving mitochondrial dysfunction including heart disease, neurodegenerative disorders, and cancer.

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Gender difference in the activity but not expression of estrogen receptors α and β in human lung adenocarcinoma cells

Cited by 89 publications

References 86 publications

The Estrogen Receptor Pathway in Rhabdomyosarcoma: A Role for Estrogen Receptor-β in Proliferation and Response to the Antiestrogen 4′OH-Tamoxifen

The Estrogen Receptor Pathway in Rhabdomyosarcoma: A Role for Estrogen Receptor-β in Proliferation and Response to the Antiestrogen 4′OH-Tamoxifen

Identification of transcriptional regulatory elements in the human somatostatin receptor sst2 promoter and regions including estrogen response element half-site for estrogen activation

Regulation of nuclear respiratory factor-1 expression by 17beta-estradiol : a new mechanism for coordinating mitochondrial gene expression.

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