scholarly journals Estrogen receptor regulates insulin-like growth factor-I receptor gene expression in breast tumor cells: involvement of transcription factor Sp1

2006 ◽  
Vol 191 (3) ◽  
pp. 605-612 ◽  
Author(s):  
Sharon Maor ◽  
Doris Mayer ◽  
Ronit I Yarden ◽  
Adrian V Lee ◽  
Rive Sarfstein ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Estrogen Receptor ◽  
Transcription Factor ◽  
Receptor Gene ◽  
Luciferase Reporter ◽  
Cancer Etiology ◽  
Estradiol Treatment ◽  
Igf I ◽  
Mcf 7

The insulin-like growth factors, IGF-I and IGF-II are a familyof mitogenic polypeptides with important roles in growth and differentiation. The biological actions of the IGFs are mediated by the IGF-I receptor (IGF-IR), a cell-surface tyrosine kinase, whose activation by serum IGF-I seems to be a key step in breast cancer initiation. Evidence accumulated indicates that estrogens stimulate the expression and activity of IGF axis components. The aim of our study was to examine the transcriptional mechanisms involved in regulation of IGF-IR gene expression by the estrogen receptor (ER). For this purpose, transient transfections using an IGF-IR promoter-luciferase reporter plasmid were performed in breast cancer-c derived ER-positive MCF-7 cells and isogenic ER-negative C4 cells. To examine the potential involvement of zinc-finger nuclear proteins in the transactivating effect of estrogens, chromatin immunoprecipitation (ChIP) experiments were performed using an Sp1 antibody, along with the Sp1-family-binding inhibitor Mithramycin A. The results obtained indicate that basal IGF-IR promoter activity was 5.8-fold higher in MCF-7 than in C4 cells. Estradiol treatment significantly activated the IGF-IR promoter in MCF-7, but not in C4 cells. Furthermore, the estrogen responsive region in the IGF-IR promoter was mapped to a GC-rich sequence located between nucleotides −40 and −188 in the 5′ flanking region. ChIP experiments revealed that at least part of the estrogen effect on IGF-IR expression was mediated through activation of the Sp1 transcription factor. In summary, our studies demonstrate that IGF-IR gene transcription in breast cancer cells is controlled by interactions between ERα and Sp1. Dysregulated expression of the IGF-IR gene may have pathologic consequences with relevance in breast cancer etiology.

scholarly journals Identification of Gene Expression Signature in Estrogen Receptor Positive Breast Carcinoma

2010 ◽  
Vol 2 ◽  
pp. BIC.S3793 ◽  
Author(s):  
Arvind D. Thakkar ◽  
Hemanth Raj ◽  
Debarshi Chakrabarti ◽  
Ravishankar ◽  
N. Saravanan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Estrogen Receptor ◽  
Transcription Factor ◽  
Molecular Basis ◽  
Clinical Specimen ◽  
Gene Expression Signature ◽  
Breast Tumors ◽  
Significant Group ◽  
Six Genes

A significant group of patient with estrogen receptor (ER) α positive breast tumors fails to appreciably respond to endocrine therapy. An increased understanding of the molecular basis of estrogen-mediated signal transduction and resultant gene expression may lead to novel strategies for treating breast cancer. In this study, we sought to identify the dysregulated genes in breast tumors related to ERα status. Microarray analyses of 31 tumor samples showed 108 genes differentially expressed in ERα (+) and ERα (–) primary breast tumors. Further analyses of gene lists indicated that a significant number of dysregulated genes were involved in mRNA transcription and cellular differentiation. The majority of these genes were found to have promoter-binding sites for E74-like factor 5 (ELF5; 54.6% genes), E2F transcription factor 1 (E2F1; 22.2% genes), and nuclear transcription factor Y alpha (NFYA; 32.4% genes). Six candidate genes ( NTN4, SLC7A8, MLPH, ENPP1, LAMB2, and PLAT) with differential expression were selected for further validation studies using RT-qPCR (76 clinical specimen) and immunohistochemistry (48 clinical specimen). Our studies indicate significant overexpression of all the six genes in ERα (+) breast tumors as compared to ERα (–) breast tumors. In vitro studies using T-47D breast cancer cell line confirmed the estrogen dependant expression of four of the above six genes ( SLC7A8, ENPP1, LAMB2, and PLAT). Collectively, our study provides further insights into the molecular basis of estrogen-dependent breast cancer and identifies “candidate biomarkers” that could be useful for predicting endocrine responsiveness.

scholarly journals Regulation of estrogen receptor-? gene expression by 1,25-dihydroxyvitamin D in MCF-7 cells

1999 ◽  
Vol 75 (4) ◽  
pp. 640-651 ◽  
Author(s):  
Adriana Stoica ◽  
Miguel Saceda ◽  
Amina Fakhro ◽  
Harrison B. Solomon ◽  
Bradley D. Fenster ◽  
...  
Keyword(s):  
Gene Expression ◽  
Estrogen Receptor ◽  
Receptor Gene ◽  
Estrogen Receptor Gene ◽  
Dihydroxyvitamin D ◽  
1,25 Dihydroxyvitamin D ◽  
Receptor Gene Expression ◽  
Mcf 7

scholarly journals Spatholobus suberectusColumn Extract Inhibits Estrogen Receptor Positive Breast Cancer via Suppressing ER MAPK PI3K/AKT Pathway

2016 ◽  
Vol 2016 ◽  
pp. 1-13 ◽  
Author(s):  
Jia-Qi Sun ◽  
Gan-Lin Zhang ◽  
Yi Zhang ◽  
Nan Nan ◽  
Xu Sun ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Chinese Herb ◽  
Luciferase Reporter ◽  
Akt Pathway ◽  
G1 Phase ◽  
Reporter System ◽  
Estrogen Receptor Positive ◽  
Spatholobus Suberectus ◽  
Mcf 7

Although Chinese herbal compounds have long been alternatively applied for cancer treatment in China, their treatment effects have not been sufficiently investigated. The Chinese herbSpatholobus suberectusis commonly prescribed to cancer patients. HPLC analysis has shown that the main components ofSpatholobus suberectusare flavonoids that can be classified as phytoestrogens, having a structure similar to estrogen. This study was designed to investigate the effects ofSpatholobus suberectuscolumn extract (SSCE) on the estrogen receptor-positive (ER+) breast cancer cell line MCF-7 and its possible molecular mechanism. In our study, MTT assay was performed to evaluate cell viability. The results show that SSCE (80, 160, and 320 μg/ml) significantly decreased the viability of MCF-7 cells. SSCE also triggered apoptosis, arrested the cell cycle at the G0/G1 phase, and inhibited cell migration. A dual-luciferase reporter system showed that SSCE suppressed intranuclear p-ER activity; Western blot analysis confirmed the repressed expression of phosphorylated-ER alpha (p-ERα), ERK1/2, p-ERK1/2, AKT, p-AKT, p-mTOR, PI3K, and p-PI3K, indicating that SSCE suppressed the MAPK PI3K/AKT signaling pathway. Collectively, our results suggest that SSCE causes apoptosis, an arrest in the G0/G1 phase, and a decrease in migration in ER+ MCF-7 cells via hypoactivity of the ER and suppression of the MAPK PI3K/AKT pathway.

scholarly journals Role of estrogen receptor (ER) α in insulin-like growth factor (IGF)-I-induced responses in MCF-7 breast cancer cells

2005 ◽  
Vol 35 (3) ◽  
pp. 433-447 ◽  
Author(s):  
S Zhang ◽  
X Li ◽  
R Burghardt ◽  
R Smith ◽  
S H Safe
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Growth Factor ◽  
Breast Cancer Cells ◽  
S Phase ◽  
Induced Responses ◽  
Igf I ◽  
Phase Progression ◽  
Mcf 7

Insulin-like growth factor-I (IGF-I) is a mitogenic polypeptide that induces proliferation of MCF-7 breast cancer cells, and cotreatment with the phosphoinositide 3-kinase (PI3-K) inhibitor LY294002 and the antiestrogen ICI 182780 inhibits IGF-I-induced growth. The role of estrogen receptor α (ERα) in mediating responses induced by IGF-I was investigated in cells transfected with small inhibitory RNA for ERα (iERα). The results showed that IGF-I-dependent phosphorylation of Akt and mitogen-activated protein kinase, induction of G1–S-phase progression and enhanced expression of cyclin D1 and cyclin E were dependent on ERα. Moreover, these same IGF-I-induced responses were also inhibited by the antiestrogen ICI 182780 and this was in contrast to a previous report suggesting that ICI 182780 did not affect IGF-I-dependent activation of PI3-K or induction of cyclin D1 expression. ICI 182780 exhibits antimitogenic activity and iERα inhibits G1–S-phase progression and proliferation of MCF-7 cells treated with IGF-I, suggesting that the effects of the antiestrogen are primarily related to downregulation of ERα.

scholarly journals Transcriptome profiling reveals bisphenol A alternatives activate estrogen receptor alpha in human breast cancer cells

2017 ◽  
Author(s):  
Robin Mesnage ◽  
Alexia Phedonos ◽  
Matthew Arno ◽  
Sucharitha Balu ◽  
J. Christopher Corton ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Estrogen Receptor ◽  
Human Breast Cancer ◽  
Breast Cancer Cells ◽  
Estrogenic Activity ◽  
Human Breast Cancer Cell ◽  
Human Breast Cancer Cells ◽  
Human Breast ◽  
Mcf 7

AbstractBackgroundPlasticizers with estrogenic activity, such as bisphenol A (BPA), have been reported to have potential adverse health effects in humans. Due to mounting evidence of these health effects and public pressure, BPA is being phased out by the plastics manufacturing industry and replaced by other bisphenol variants in “BPA-free” products.ObjectivesWe have compared estrogenic activity of BPA to 6 bisphenol analogues (bisphenol S, BPS; bisphenol F, BPF; bisphenol AP, BPAP; bisphenol AF, BPAF; bisphenol Z, BPZ; bisphenol B, BPB) in three human breast cancer cell lines.MethodsEstrogenicity was assessed by cell growth in an estrogen receptor (ER)-mediated cell proliferation assay, and by the induction of estrogen response element (ERE)-mediated transcription in a luciferase assay. Gene expression profiles were determined in MCF-7 human breast cancer cells by microarray analysis and confirmed by Illumina-based RNA sequencing.ResultsAll bisphenols showed estrogenic activity in promoting cell growth and inducing ERE-mediated transcription. BPAF was the most potent bisphenol, followed by BPB > BPZ ~ BPA > BPF ~ BPAP > BPS. The addition of ICI 182,780 antagonized the activation of ERs by bisphenols. Data mining of ToxCast high-throughput screening assays confirms our results but also shows divergence in the sensitivities of the assays. The comparison of transcriptome profile alterations resulting from BPA alternatives with an ERα gene expression biomarker further indicates that all BPA alternatives act as ERα agonists in MCF-7 cells. These results were confirmed by RNA sequencing.ConclusionIn conclusion, BPA alternatives are not necessarily less estrogenic in a human breast cancer cell model. Three bisphenols (BPAF, BPB, and BPZ) were more estrogenic than BPA. The relevance of human exposure to BPA alternatives in hormone-dependent breast cancer risk should be investigated.

scholarly journals Estradiol Reduces Nonclassical Transcription at Cyclic Adenosine 3′,5′-Monophosphate Response Elements in Glioma Cells Expressing Estrogen Receptor Alpha

Endocrinology ◽  
2006 ◽  
Vol 147 (4) ◽  
pp. 1796-1804 ◽  
Author(s):  
Andrew J. Mhyre ◽  
Robert A. Shapiro ◽  
Daniel M. Dorsa
Keyword(s):  
Gene Expression ◽  
Estrogen Receptor ◽  
Reporter Gene ◽  
Glioma Cells ◽  
Luciferase Reporter ◽  
Estradiol Treatment ◽  
Camp Response Element ◽  
Response Element ◽  
Functional Changes ◽  
Rapid Signaling

Estradiol can protect the brain from a variety of insults by activating membrane-initiated signaling pathways, and thereby modulate gene expression and lead to functional changes in neurons. These direct neuronal effects of the hormone have been well documented; however, it is less understood what effects estradiol may have on nonneuronal cells of the central nervous system. There is evidence that estradiol levels can induce the release of glial-derived growth factors and other cytokines, suggesting that estradiol may both directly and indirectly protect neurons. To determine whether 17β-estradiol (E2) can activate rapid signaling and modulate nonclassical transcription in astrocytes, we stably transfected the C6 rat glioblastoma cell line with human estrogen receptor (ER) α (C6ERα) or rat ERβ (C6ERβ). Introduction of a cAMP response element-luciferase reporter gene into C6, C6ERα, and C6ERβ cells leads to the observation that E2 treatment reduced isoproterenol-stimulated luciferase activity by 35% in C6ERα but had no effect on reporter gene expression in C6ERβ or untransfected C6 cells. A similar effect was seen with a membrane-impermeable estrogen (E2-BSA), suggesting the modulation of nonclassical transcription by estradiol treatment is mediated by the activation of a membrane-initiated signaling pathway. Furthermore, pretreatment with wortmannin (phosphatidylinsositol 3-kinase) or U73122 (phospholipase C) attenuated the E2-induced reduction in nonclassical transcription. We conclude that E2 treatment reduces cAMP response element-mediated transcription in glioma cells expressing ERα and that this reduction is dependent on the activation of membrane-initiated signaling. These findings suggest a novel model of estrogen rapid signaling in astrocytes that leads to modulation of nonclassical transcription.

scholarly journals Stable Inhibition of Specific Estrogen Receptor α (ERα) Phosphorylation Confers Increased Growth, Migration/Invasion, and Disruption of Estradiol Signaling in MCF-7 Breast Cancer Cells

Endocrinology ◽  
2012 ◽  
Vol 153 (9) ◽  
pp. 4144-4159 ◽  
Author(s):  
B. P. Huderson ◽  
T. T. Duplessis ◽  
C. C. Williams ◽  
H. C. Seger ◽  
C. G. Marsden ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Estrogen Receptor ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Target Genes ◽  
Expression Patterns ◽  
Estrogen Receptor Α ◽  
Regulated Gene Expression ◽  
Mcf 7

Elevated phosphorylation of estrogen receptor α (ERα) at serines 118 (S118) and 167 (S167) is associated with favorable outcome for tamoxifen adjuvant therapy and may serve as surrogate markers for a functional ERα signaling pathway in breast cancer. It is possible that loss of phosphorylation at S118 and/or S167 could disrupt ERα signaling, resulting in aggressive ERα-independent breast cancer cells. To this end, MCF-7 breast cancer cells were stably transfected with an ERα-specific short hairpin RNA that reduced endogenous ERα. The resulting cell line was stably transfected with wild-type ERα (ER-AB cells), or ERα containing serine to alanine mutation at S118 or S167 (S118A cells and S167A cells, respectively). These stable cell lines expressed approximately equivalent ERα compared with parental MCF-7 cells and were evaluated for growth, morphology, migration/invasion, and ERα-regulated gene expression. S118A cells and S167A cells exhibited increased growth and migration/invasion in vitro. Forward- and side-scatter flow cytometry revealed that S167A cells were smaller in size, and both S118A and S167A cells exhibited less cellular complexity. S118A and S167A cells expressed pancytokeratin and membrane localization of β-catenin and did not express vimentin, indicating retention of epithelial lineage markers. Expression of ERα-target genes and other genes regulated by ERα signaling or involved in breast cancer were markedly altered in both S118A and S167A cells. In summary, attenuated phosphorylation of ERα at S118 and S167 significantly affected cellular physiology and behavior in MCF-7 breast cancer cells, resulting in increased growth, migration/invasion, compromised expression of ERα target genes, and markedly altered gene expression patterns.

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