| HOME | HELP | CONTACT US | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
1 Group on Hormones and Signal Transduction, German Cancer Research Center, Heidelberg D-69120, Germany
2 Laboratory of Genomic Applications, Chaim Sheba Medical Center, Tel Hashomer 52621, Israel
3 Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA
4 Department of Oncological Surgery, Chaim Sheba Medical Center, Tel Hashomer 52621, Israel
(Requests for offprints should be addressed to H Werner; Email: hwerner{at}post.tau.ac.il)
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
and Sp1. Dysregulated expression of the IGF-IR gene may have pathologic consequences with relevance in breast cancer etiology. |
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Solid evidence accumulated in recent years indicating that the biological activity of the IGF system is strongly associated with estrogen status (Lee et al. 1999, Yee & Lee 2000). Estrogens were shown to increase IGF-I binding and IGF-IR mRNA levels in MCF-7 cells by sevenfold, suggesting that the potential mechanism by which estrogens stimulate breast cancer cell proliferation involves sensitization to the mitogenic effects of IGFs by enhancing IGF-IR concentration (Stewart et al. 1990). In addition, estrogens can modulate IGF signaling by regulating the expression of other members of the IGF family, including ligands, IGFBPs, and insulin receptor substrate (IRS)-1 (Osborne et al. 1989, McGuire et al. 1992, Salerno et al. 1999). Using MCF-7-derived sublines that have been selected for loss of estrogen receptor (ER) by long-term estrogen withdrawal, it was previously demonstrated that the loss of ER caused reduced expression of IGF-signaling molecules and failure to proliferate in response to IGF-I or estrogen. Re-expression of ER restored the IGF-responsive phenotype, suggesting that ER is a crucial regulator of the IGF mitogenic loop (Oesterreich et al. 2001).
The IGF-IR promoter is a TATA-less, CAAT-less, and initiator type of promoter. The region flanking the transcription start site is extremely GC-rich, and contains numerous potential binding sites for transcription factor Sp1, a zinc-finger-containing nuclear protein that has been shown to strongly transactivate the IGF-IR promoter (Beitner-Johnson et al. 1995). Given the involvement of ER in control of IGF-IR gene expression and IGF-I action, and in view of the fact that the transcriptional mechanisms involved in regulation of the IGF-IR gene by ER have not yet been characterized, the present study was designed to analyze the molecular mechanisms responsible for regulation of the IGF-IR gene by ER. Specifically, we hypothesized that ER regulates IGF-IR gene expression through interaction with transcription factor Sp1. The results obtained prove that ER is a potent transactivator of the IGF-IR gene and that GC-rich sequences in the proximal IGF-IR promoter region are required for this effect. Impaired interactions between ER and zinc-finger proteins may lead to aberrant IGF-IR expression in breast cancer cells.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The MCF-7 human breast cancer cell line was maintained in Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 10% fetal bovine serum (FBS), 2 mM glutamine, and 50 µg/ml gentamicin sulfate. C4 cells were generated by clonal selection of MCF-7 cells, cultured in estrogen-free medium for 9 months (Oesterreich et al. 2001). C4 cells were kindly provided by Dr Wade V Welshons (University of Missouri, Columbia, MO, USA). The C4 cell line was maintained in DMEM without phenol red supplemented with 10% charcoal-stripped FBS, 2 mM glutamine, and 50 µg/ml gentamicin sulfate.
Western immunoblots
Cells were serum-starved overnight and then incubated with increasing concentrations of ß-estradiol (Sigma-Aldrich Corp.) for 24 h. Following incubation, cells were harvested and lysates were prepared as described previously (Idelman et al. 2002). Samples (50 µg) were subjected to 8% SDS-PAGE, followed by electrophoretic transfer of the proteins to nitrocellulose membranes. After blocking with 3% bovine serum albumin or milk in T-TBS (20 mM Tris–HCl, pH 7.5, 135 mM NaCl, and 0.1% Tween-20), blots were incubated with polyclonal antibodies against IGF-IR ß subunit, Sp1 and ER (C-20, PEP-2, and MC-20 respectively; Santa Cruz Biotechnology, Santa Cruz, CA, USA), and against actin or tubulin, followed by incubation with a horseradish peroxidase-conjugated secondary antibody. Proteins were detected using the SuperSignal West Pico Chemiluminescent Substrate (Pierce, Rockford, IL, USA). In selected experiments, the Sp1-family inhibitor Mithramycin A (Sigma-Aldrich Corp.) was added at a concentration of 500 nM 1 h before the estradiol treatment.
IGF-IR promoter activity measurements
For transient transfection experiments, luciferase reporter constructs p(–2350/+640)LUC, p(–476/+640)LUC, p(–188/+640)LUC, and p(–40/+640)LUC (nucleotide 1 corresponds to the transcription start site) were employed. These plasmids include 2350, 476, 188, or 40 nucleotides of the 5'-flanking region, linked to 640 bp of the 5'-untranslated region of the rat IGF-IR gene. The basal promoter activities of these constructs were previously reported (Maor et al. 2000). The ER expression vector was generated by subcloning the human ER cDNA into the pSG5 vector using EcoRI sites. The ER vector was provided by Dr Yitzhak Koch, Weizmann Institute of Science, Rehovot, Israel. An Sp1 expression vector (pPacSp1), under the control of an actin promoter in the pPac0 vector, was provided by Dr Robert Tjian (University of California, Berkeley, CA, USA). Cells were seeded in six-well plates 48 h before transfection, and transfected with 0.5 µg of the indicated IGF-IR promoter reporter plasmids, along with 1.3 µg ER expression vector (or empty pSG5 vector), 1 µg pPacSp1 (or empty pPac0 vector), and 0.2 µg ß-galactosidase expression plasmid (pCMVß, Clontech, Palo Alto, CA, USA), using the jetPEI reagent (Polyplus Transfection, Illkirch, France). Twenty-four hours after transfection, cells were treated with estradiol (1, 10 and 100 nM) or left untreated. Cells were harvested after an additional 24 h, and luciferase and ß-galactosidase activities were measured as previously described (Maor et al. 2000). In addition, some experiments included Mithramycin A. Mithramycin A was added 1 h before estradiol treatment at a concentration of 500 nM.
Chromatin immunoprecipitation (ChIP) studies
Estradiol-treated and untreated cultures were incubated with formaldehyde (1% final concentration) for 10 min at room temperature. At the end of the incubation period, cells were washed twice and harvested using ice-cold phosphate-buffered saline. Pelleted cells were resuspended in 1% SDS-containing buffer, incubated on ice for 10 min, and sonicated for 3 min. Cell extracts were then immunoprecipitated with anti-Sp1 or anti-ER for 18 h at 4 °C. For PCR analysis of Sp1/ER-immunoprecipitated chromatin, a set of primers encompassing the IGF-IR proximal promoter region (nt –458 to +53) was employed, using the following primers: sense, 5'-CTTTCCAGCCGCGCTGTTGTTG-3'; anti-sense, 5'-GGTAAACAAGAGCCCCAGCCTC-3'. Sequencing analyzes revealed the presence of cis-acting elements for transcription factor Sp1 in this particular region (Cooke et al. 1991). PCR was performed using the TermalAce DNA polymerase (InVitrogen).
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
To evaluate the potential role of ER on IGF-IR levels, we employed the human breast cancer-derived MCF-7 (ER-positive) and MCF-7-derived C4 (ER-negative) cell lines. C4 cells were generated by clonal selection of MCF-7 cells that were maintained for 9 months in estrogen-free culture medium (Oesterreich et al. 2001). Although C4 cells exhibited certain variability in ER expression, the passages used in the present study displayed consistently low levels of ER (Fig. 1a
). Results of western immunoblots using an anti-IGF-IR ß-subunit antibody showed that IGF-IR levels in ER-depleted C4 cells were 13.6% of those in control MCF-7 cells (Fig. 1a). These results replicate previously reported results (Reizner et al. 2005). To address the responsiveness of MCF-7 and C4 cells to estradiol treatment, cells were serum-starved overnight and then stimulated with increasing concentrations of estradiol for 24 h, after which cell lysates were prepared. Western blot analysis revealed that estradiol stimulated precursor and mature IGF-IR levels in MCF-7 cells in a dose-dependent manner (Fig. 1b and c), whereas no changes were seen in C4 cells (Fig. 1b). Maximal stimulation was achieved at a dose of 100 nM estradiol (3.3-and 7-fold increase in mature and pre-IGF-IR levels respectively).
|
To establish whether the differences in IGF-IR gene expression between ER-positive and ER-negative cells are mediated at the level of transcription, MCF-7 and C4 cell lines were transiently transfected with a luciferase reporter construct under the control of the proximal IGF-IR promoter region (p(–476/+640)LUC). Transfected cells were incubated in the absence or presence of estradiol (100 nM) during the last 24 h of the incubation period. Forty-eight hours after transfection, cells were harvested and luciferase and ß-galactosidase activities were measured. The results obtained indicated that basal IGF-IR promoter activity was 5.8-fold higher in MCF-7 than in C4 cells. In addition, estradiol activated IGF-IR promoter in MCF-7 cells (1.9-fold), whereas it had no effect in C4 cells (Fig. 2a). Furthermore, coexpression of C4 cells with an ER expression vector did not confer upon the cells the ability to respond to estradiol (Fig. 2b).
|
To define the IGF-IR promoter regions responsible for mediating the observed transcriptional activity of ER in MCF-7 cells, cotransfections were performed using a series of IGF-IR promoter deletion constructs containing different portions of 5'-flanking and 5'-untranslated regions (Fig. 3a), along with the ER expression vector. Twenty-four hours after transfection cells were treated with estradiol for an additional 24 h (or left untreated) and, after an additional 24 h cells were harvested and luciferase and ß-galactosidase values were measured. Results of deletion analysis showed that estrogen-stimulated promoter activity of the p(–476/+ 640)LUC and p(–188/+640)LUC constructs by 2.8- and 2.4-fold respectively. The basal promoter activity of the full-length p(–2350/+640)LUC construct was twofold lower than that of the proximal p(–476/+640)LUC plasmid, but was still responsive to estradiol stimulation. Removal of the promoter fragment located between –188 and –40 completely abrogated the stimulatory effect of estradiol, suggesting that the estrogen responsive region in the IGF-IR promoter was mapped to a fragment located between nucleotides –188 and –40 in the 5' flanking region (Fig. 3b).
|
Previous studies have identified a number of Sp1-binding sites in the IGF-IR promoter region (Beitner-Johnson et al. 1995). To begin to examine the potential involvement of transcription factor Sp1 in the ER-induced IGF-IR expression, we measured Sp1 levels in MCF-7 and C4 cells. To this end, cells were serum-starved overnight and then stimulated with increasing concentrations of estradiol for 24 h, after, which cell lysates were prepared. Western blot analysis revealed that basal Sp1 levels in MCF-7 cells were twofold higher than in C4 cells. No starvation-induced decrease in Sp1 levels was seen at 24 h (data not shown). As shown in Fig. 4a, no change in Sp1 levels was seen after estradiol treatment. To more directly evaluate whether Sp1 is involved in ER action, we cotransfected C4 cells with an Sp1 expression vector (or empty pPac0), in the presence of the ER expression vector (or empty pSG5) and the p(–476/+640)LUC reporter construct. Luciferase measurements revealed that, in the presence of Sp1, ER-stimulated IGF-IR promoter activity by 2.2-fold compared with cells transfected with Sp1 or ER alone (Fig. 4b).
|
).
|
, and the IGF-IR promoter
Next, the potential physical interactions between Sp1, ER, and the IGF-IR promoter region were assessed using ChIP assays. Untransfected MCF-7 and C4 cells were incubated with estradiol (100 nM) for 24 h (or left untreated, for control purposes), after which cells were processed as described under Materials and Methods. Cell lysates were immunoprecipitated with anti-Sp1 or anti-ER and the precipitated chromatin was amplified by PCR using primers encompassing nt –458 to +53 of the IGF-IR promoter. Results of ChIP assays showed that estradiol treatment enhanced Sp1 binding to the IGF-IR promoter region in MCF-7 cells by 194% and ER binding by 187% (Fig. 5b and c
). No ER binding to the IGF-IR promoter was detected in C4 cells (data not shown).
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The results obtained show that ER status is strongly correlated with IGF-IR levels and that estradiol is a potent inducer of IGF-IR expression. Furthermore, results of transient transfection experiments show that the effect of estradiol on IGF-IR levels is mediated at the transcriptional level. In addition, deletion analysis using a series of IGF-IR promoter constructs containing different portions of 5'-flanking and 5'-untranslated regions shows that removal of the promoter fragment located between –188 and –40 completely abrogated the stimulatory effect of estradiol, suggesting that the estrogen responsive region in the IGF-IR promoter was mapped to a proximal promoter fragment located between nucleotides –40 and –188. Taken together, our results are consistent with those of Bartucci et al.(2001) showing that IGF-IR growth-related functions in breast cancer cells depend on ER expression. Interestingly, the basal activity of the full-length IGF-IR promoter (p(–2350/+640)LUC) is significantly lower than that of proximal promoter fragments (p(–476/+640)LUC and p(–188/+640)LUC). These results are consistent with the existence of still unidentified silencer element/s in the distal promoter region. However, the biological role of these elements as well as their potential interactions with ER and Sp1 are yet to be elucidated.
The classical estrogen response element (ERE) consensus sequence was originally defined as GGTCANNNTGACC and shown to be directly bound by ER. However, several estrogen-responsive genes have been identified that utilize divergent EREs, or even other transcription factor DNA-binding sites as the target sequence for ER action. This family of genes includes those in which the effect of ER is mediated through activating protein-1, zinc-finger protein Sp1, or nuclear factor-
B (NF-B), and others in, which ER is thought to act through as yet unidentified protein/s (Zou et al. 1999).
Previous studies have identified transcription factor Sp1 as a critical transactivator of the IGF-IR gene (Beitner-Johnson et al. 1995). The IGF-IR promoter region includes multiple Sp1-binding sites, whose presence is crucial for Sp1 transactivation. Interestingly, Sp1 levels in ER-positive MCF-7 cells were significantly higher than in ER-negative C4 cells. No change in Sp1 levels, however, was seen following estradiol treatment. Expression of Sp1 in conjunction with ER, but not ER alone, in C4 cells, induced a strong stimulation of IGF-IR promoter activity. These results are consistent with a crucial role for Sp1 in the ER-induced IGF-IR gene transactivation. The important role of Sp1 is further corroborated by results of experiments showing that Mithramycin A treatment abrogated the estradiol-stimulated increase in IGF-IR promoter activity. In addition, estradiol enhanced both Sp1 and ER binding to the IGF-IR promoter region in MCF-7 cells, whereas no ER binding was detected in C4 cells. Additional genes shown to be regulated by ER/Sp1 include IGFBP-4, cyclin D1, adenosine deaminase, retinoic acid receptor 1, c-fos, cathepsin D, E2F1, transforming growth factor , progesterone receptor, epidermal growth factor receptor, vascular endothelial growth factor, and others (Duan et al. 1998, Sun et al. 1998, Qin et al. 1999, Wang et al. 1999, 2001, Xie et al. 1999, Petz & Nardulli 2000, Salvatori et al. 2000, Vyhlidal et al. 2000, Castro-Rivera et al. 2001, Safe 2001, Khan et al. 2003, Kim et al. 2005, Koos et al. 2005). Interestingly, results of fluorescence resonance energy transfer assays are consistent with in vitro studies on ER/Sp1 interactions and transactivation, and confirmed that ER and Sp1 interact in living breast cancer cells (Kim et al. 2005). Of notice, Oesterreich et al.(2001) reported that expression of ER in C4 cells restored estrogen inducibility of the IGF-IR, whereas in the present study we were able to restore estrogen responsiveness in C4 cells only by coexpression of an Sp1 vector, in addition to ER. The discrepancy between the results can be most probably explained by the fact that in the present study we employed transient transfection assays, whereas Oesterreich et al.(2001) used stable transfected clones.
Our bioinformatic analyzes, as well as a report by Scheidegger et al.(2000), indicate that there is no consensus EREs in the IGF-IR promoter. Consistently, using EMSA assays Scheidegger et al.(2000) were unable to demonstrate direct binding of ER to sequences in the IGF-IR promoter in rat aortic smooth muscle cells. It is conceivable, however, that half-EREs, which are present in this region, might be involved in this interaction (Vyhlidal et al. 2000, Koos et al. 2005). The results of ChIP experiments using an ER antibody in the present study suggest that ER binds to the IGF-IR promoter via Sp1, and that both proteins can form a DNA-binding high molecular weight complex. We have previously demonstrated that transcription of the IGF-IR gene in breast cancer cells is negatively regulated by breast cancer susceptibility gene, BRCA1 (Maor et al. 2000). The mechanism of action of BRCA1 was shown to involve specific binding to Sp1, thus preventing this zinc-finger protein from binding to, and transactivating, the IGF-IR promoter (Abramovitch & Werner 2003). We speculate that Sp1 is a central player in transcriptional regulation of the IGF-IR gene that mediates the actions of both proliferative agents (e.g. estrogens) as well as tumor suppressors (e.g. BRCA1). Furthermore, the estrogen-induced downregulation of IGF-IR expression in vascular smooth muscle cells was also shown to involve binding of ER to Sp1, thus preventing Sp1 binding to the IGF-IR promoter (Scheidegger et al. 2000).
In summary, our results demonstrate that estradiol activates the IGF-IR promoter in an ER-dependent manner. 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. In addition, activation of the Sp1 transcription factor is a critical step in estrogen-induced IGF-IR gene expression. Dysregulation of the IGF-IR gene may constitute a key step in breast cancer initiation and progression.
|
Acknowledgements |
|---|
|
Funding |
|---|
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Arteaga CL, Kitten LJ, Coronado EB, Jacobs S, Kull FC Jr, Allerd DC & Osborne CK 1989 Blockade of the type I somatomedin receptor inhibits growth of human breast cancer cells in athymic mice. Journal of Clinical Investigation 84 1418–1423.[Web of Science][Medline]
Bartucci M, Morelli C, Mauro L, Ando S & Surmacz E 2001 Differential insulin-like growth factor I receptor signaling and function in estrogen receptor (ER)-positive MCF-7 and ER-negative MDA-MB-231 breast cancer cells. Cancer Research 61 6747–6754.
Baserga R 1999 The IGF-I receptor in cancer research. Experimental Cell Research 253 1–6.[CrossRef][Web of Science][Medline]
Baserga R, Hongo A, Rubini M, Prisco M & Valentinis B 1997 The IGF-I receptor in cell growth, transformation and apoptosis. Biochimica et Biophysica Acta 1332 F105–F126.[Medline]
Beitner-Johnson D, Werner H, Roberts CT Jr & LeRoith D 1995 Regulation of insulin-like growth factor I receptor gene expression by Sp1: physical and functional interactions of Sp1 at GC boxes and at a CT element. Molecular Endocrinology 9 1147–1156.
Castro-Rivera E, Samudio I & Safe S 2001 Estrogen regulation of cyclin D1 gene expression in ZR-75 breast cancer cells involves multiple enhancer elements. Journal of Biological Chemistry 276 30853–30861.
Cooke DW, Bankert LA, Roberts CT Jr, LeRoith D & Casella SJ 1991 Analysis of the human type I insulin-like growth factor receptor promoter region. Biochemical and Biophysical Research Communications 177 1113–1120.[CrossRef][Web of Science][Medline]
Duan R, Porter W & Safe S 1998 Estrogen-induced c-fos protooncogene expression in MCF-7 human breast cancer cells: role of estrogen receptor Sp1 complex formation. Endocrinology 139 1981–1990.
Hankinson SE, Willett WC, Colditz GA, Hunter DJ, Michaud DS, Deroo B, Rosner B, Speizer FE & Pollak M 1998 Circulating concentrations of insulin-like growth factor-I and risk of breast cancer. Lancet 351 1393–1396.[CrossRef][Web of Science][Medline]
Idelman G, Glaser T, Roberts CT Jr & Werner H 2002 WT1-p53 interactions in insulin-like growth factor-I receptor gene regulation. Journal of Biological Chemistry 278 3474–3482.
Khan S, Abdelrahim M, Samudio I & Safe S 2003 Estrogen receptor/Sp1 complexes are required for induction of cad gene expression by 17beta-estradiol in breast cancer cells. Endocrinology 144 2325–2335.
Kim K, Barhoumi R, Burghardt R & Safe S 2005 Analysis of estrogen receptor alpha-Sp1 interactions in breast cancer cells by fluorescence resonance energy transfer. Molecular Endocrinology 19 843–854.
Koos RD, Kazi AA, Roberson MS & Jones JM 2005 New insight into the transcriptional regulation of vascular endothelial growth factor expression in the endometrium by estrogen and relaxin. Annals of the New York Academy of Sciences 1041 233–247.[CrossRef][Web of Science][Medline]
Lee AV, Jackson JG, Gooch JL, Hilsenbeck SG, Coronado-Heinsohn E, Osborne CK & Yee D 1999 Enhancement of insulin-like growth factor signaling in human breast cancer: estrogen regulation of insulin receptor substrate-1 expression in vitro and in vivo. Molecular Endocrinology 13 787–796.
LeRoith D, Werner H, Beitner-Johnson D & Roberts CT Jr 1995 Molecular and cellular aspects of the insulin-like growth factor I receptor. Endocrine Reviews 16 143–163.
Maor SB, Abramovitch S, Erdos MR, Brody LC & Werner H 2000 BRCA1 suppresses insulin-like growth factor-I receptor promoter activity: potential interaction between BRCA1 and Sp1. Molecular Genetics and Metabolism 69 130–136.[CrossRef][Web of Science][Medline]
McGuire W, Jackson JG, Figueroa JA, Shimasaki SA, Powell DR & Yee D 1992 Regulation of insulin-like growth factor-binding protein (IGFBP) expression by breast cancer cells: use of IGFBP-1 as an inhibitor of insulin-like growth factor action. Journal of the National Cancer Institute 84 1336–1341.
Oesterreich S, Zhang P, Guler RL, Sun X, Curran EM, Welshons WV, Osborne CK & Lee AV 2001 Re-expression of estrogen receptor alpha in estrogen receptor alpha-negative MCF-7 cells restores both estrogen and insulin-like growth factor-mediated signaling and growth. Cancer Research 61 5771–5777.
Osborne CK, Coronado EB, Kitten LJ, Arteaga CI, Fuqua SAW, Ramasharma K, Marshall M & Li CH 1989 Insulin-like growth factor-II (IGF-II): a potential autocrine/paracrine growth factor for human breast cancer acting via the IGF-I receptor. Molecular Endocrinology 3 1701–1709.
Petz LN & Nardulli AM 2000 Sp1 binding sites and an estrogen response element half-site are involved in regulation of the human progesterone receptor A promoter. Molecular Edocrinology 14 972–985.
Pietrzkowski Z, Lammers R, Carpenter G, Soderquist AM, Limardo M, Philllips PD, Ullrich A & Baserga R 1992 Constitutive expression of insulin-like growth factor I and insulin-like growth factor I receptor abrogates all requirements for exogenous growth factors. Cell Growth and Differentiation 4 199–205.
Qin C, Singh P & Safe S 1999 Transcriptional activation of insulin-like growth factor-binding protein-4 by 17beta-estradiol in MCF-7 cells: role of estrogen receptor-Sp1 complexes. Endocrinology 140 2501–2508.
Reizner N, Maor S, Sarfstein R, Abramovitch S, Welshons WV, Curran EM, Lee AV & Werner H 2005 The WT1 Wilms’ tumor suppressor gene product interacts with estrogen receptor-alpha and regulates IGF-I receptor gene transcription in breast cancer cells. Journal of Molecular Endocrinology 35 135–144.
Sachdev D & Yee D 2001 The IGF system and breast cancer. Endocrine-Related Cancer 8 197–209.[Abstract]
Safe S 2001 Transcriptional activation of genes by 17 beta-estradiol through estrogen receptor-Sp1 interactions. Vitamins and Hormones 62 231–252.[Web of Science][Medline]
Salerno M, Sisci D, Mauro L, Guvakova MA, Ando S & Surmacz E 1999 Insulin receptor substrate 1 is a target for the pure antiestrogen ICI 182,780 in breast cancer cells. International Journal of Cancer 81 299–304.[CrossRef][Web of Science][Medline]
Salvatori L, Ravenna L, Felli MP, Cardillo MR, Russo MA, Frati L, Gulino A & Petrangeli E 2000 Identification of an estrogen-mediated deoxyribonucleic acid-binding independent transactivation pathway on the epidermal growth factor receptor gene promoter. Endocrinology 141 2266–2274.
Scheidegger KJ, Cenni B, Picard D & Delafontaine P 2000 Estradiol decreases IGF-I and IGF-I receptor expression in rat aortic smooth muscle cells. Mechanisms for its atheroprotective effects. Journal of Biological Chemistry 275 38921–38928.
Schnarr B, Strunz K, Ohsam J, Benne A, Nacker J & Mayer D 2000 Down-regulation of insulin-like growth factor-I receptor and insulin receptor substrate-1 expression in advanced human breast cancer. International Journal of Cancer 89 506–513.[CrossRef][Web of Science][Medline]
Stewart AJ, Johnson MD, May FEB & Westley BR 1990 Role of insulin-like growth factors and the type I insulin-like growth factor receptor in the estrogen-stimulated proliferation of human breast cancer cells. Journal of Biological Chemistry 265 21172–21178.
Sun G, Porter W & Safe S 1998 Estrogen-induced retinoic acid receptor alpha 1 gene expression: role of estrogen receptor-Sp1 complex. Molecular Endocrinology 12 882–890.
Surmacz E 2000 Function of the IGF-I receptor in breast cancer. Journal of Mammary Gland Biology and Neoplasia 5 95–105.[CrossRef][Web of Science][Medline]
Surmacz E, Guvakova M, Nolan M, Nicosia R & Sciacca L 1998 Type I insulin-like growth factor receptor function in breast cancer. Breast Cancer Research and Treatment 47 255–267.[CrossRef][Web of Science][Medline]
Van der Burg B, Isbrucker L, Van Selm-Miltenburg AJ, de Laat SW & Van Zoelen EJ 1990 Role of estrogen-induced insulin-like growth factors in the proliferation of human breast cancer cells. Cancer Research 50 7770–7774.
Vyhlidal C, Samudio I, Kladde M & Safe S 2000 Transcriptional activation of transforming growth factor alpha by estradiol: requirement for both a GC-rich site and an estrogen response element half-site. Journal of Molecular Endocrinology 24 329–338.[Abstract]
Wang W, Dong L, Saville B & Safe S 1999 Transcriptional activation of E2F1 gene expression by 17beta-estradiol in MCF-7 cells is regulated by NF-Y-Sp1/estrogen receptor interactions. Molecular Endocrinology 13 1373–1387.
Wang F, Samudio I & Safe S 2001 Transcriptional activation of cathepsin D gene expression by 17beta-estradiol: mechanism of aryl hydrocarbon receptor-mediated inhibition. Molecular and Cellular Endocrinology 172 91–103.[CrossRef][Web of Science][Medline]
Werner H & LeRoith D 1996 The role of the insulin-like growth factor system in human cancer. Advances in Cancer Research 68 183–223.[Web of Science][Medline]
Werner H & LeRoith D 2000 New concepts in regulation and function of the insulin-like growth factors: implications for understanding normal growth and neoplasia. Cellular and Molecular Life Sciences 57 932–942.[CrossRef][Web of Science][Medline]
Xie W, Duan R & Safe S 1999 Estrogen induces adenosine deaminase gene expression in MCF-7 human breast cancer cells: role of estrogen receptor-Sp1 interactions. Endocrinology 140 219–227.
Yee D & Lee AV 2000 Crosstalk between the insulin-like growth factors and estrogens in breast cancer. Journal of Mammary Gland Biology and Neoplasia 5 107–115.[CrossRef][Web of Science][Medline]
Yee D, Paik S, Lebovic GS, Marcus RR, Favoni RE, Cullen KJ, Lippman ME & Rosen N 1989 Analysis of insulin-like growth factor I gene expression in malignancy: evidence for a paracrine role in human breast cancer. Molecular Endocrinology 3 509–514.
Zou A, Marschke KB, Arnold KE, Berger EM, Fitzgerald P, Mais DE & Allegretto E 1999 Estrogen receptor beta activates the human retinoic acid receptor alpha-1 promoter in response to tamoxifen and other estrogen receptor antagonists, but not in response to estrogen. Molecular Endocrinology 13 418–430.
Received in final form 27 August 2006
Accepted 19 September 2006
Made available online as an Accepted Preprint 3 October 2006
This article has been cited by other articles:
|
|
 |
|
  M Udelhoven, U Leeser, S Freude, M M Hettich, M Laudes, J Schnitker, W Krone, and M Schubert Identification of a region in the human IRS2 promoter essential for stress induced transcription depending on SP1, NFI binding and ERK activation in HepG2 cells J. Mol. Endocrinol., February 1, 2010; 44(2): 99 - 113. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. KULENDRAN, M. SALHAB, and K. MOKBEL Oestrogen-Synthesising Enzymes and Breast Cancer Anticancer Res, April 1, 2009; 29(4): 1095 - 1109. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Safe and K. Kim Non-classical genomic estrogen receptor (ER)/specificity protein and ER/activating protein-1 signaling pathways J. Mol. Endocrinol., November 1, 2008; 41(5): 263 - 275. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Sun, Z. Estrov, Y. Ji, K. R. Coombes, D. H. Harris, and R. Kurzrock Curcumin (diferuloylmethane) alters the expression profiles of microRNAs in human pancreatic cancer cells Mol. Cancer Ther., March 1, 2008; 7(3): 464 - 473. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | CONTACT US | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
P < 0.01 versus MCF-7 cells. (b) C4 cells were cotransfected with the p(–476/+640)LUC reporter construct along with an ER
