Activated estrogen receptor mediates growth arrest and differentiation of a neuroblastoma cell line.

Q, Z; Spreafico, Elena; Pollio, Giuseppe; Santagati, Sabrina; Conti, Enrico; Cattaneo, Elena; Maggi, Adriana

doi:10.1073/pnas.90.8.3740

Cited by 75 publications

(60 citation statements)

References 33 publications

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“…Our demonstration of ESR1 expression in human fetal sympathetic ganglia suggests that ESR1 plays an important role during the development of the sympathetic nervous system. Furthermore, ESR1 has been reported to induce growth arrest and differentiation of NB cells following estradiol treatment (27). Our data support this finding, as we observed ESR1-mediated neuronal differentiation of SK-N-BE(2) cells.…”

Section: Discussionsupporting

confidence: 82%

“…Next, we analyzed the functional role of ESR1 expression in NB cells. Even though it is well-established that ESR1-mediated signaling contributes to proliferation of breast cancer cells (26), it has been reported that ligand-dependent activation of ESR1 in neuronal cells results in growth arrest and differentiation (27). To reaffirm this finding, we used lentiviral constructs expressing ESR1 cDNA and transduced SK-N-BE(2) cells.…”

Section: Esr1 Is Repressed By Mycn-induced Mirnas and Contributes Tomentioning

confidence: 99%

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MYCN-regulated microRNAs repress estrogen receptor-α ( ESR1 ) expression and neuronal differentiation in human neuroblastoma

Lovén

Zinin

Wahlström

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

124

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MYCN, a proto-oncogene normally expressed in the migrating neural crest, is in its amplified state a key factor in the genesis of human neuroblastoma (NB). However, the mechanisms underlying MYCN-mediated NB progression are poorly understood. Here, we present a MYCN-induced miRNA signature in human NB involving the activation and transrepression of several miRNA genes from paralogous clusters. Several family members derived from the miR-17∼92 cluster, including miR-18a and miR-19a, were among the up-regulated miRNAs. Expression analysis of these miRNAs in NB tumors confirmed increased levels in MYCN-amplified samples. Specifically, we show that miR-18a and miR-19a target and repress the expression of estrogen receptor-α (ESR1), a ligand-inducible transcription factor implicated in neuronal differentiation. Immunohistochemical staining demonstrated ESR1 expression in human fetal sympathetic ganglia, suggesting a role for ESR1 during sympathetic nervous system development. Concordantly, lentiviral restoration of ESR1 in NB cells resulted in growth arrest and neuronal differentiation. Moreover, lentiviral-mediated inhibition of miR-18a in NB cells led to severe growth retardation, outgrowth of varicosity-containing neurites, and induction of neuronal sympathetic differentiation markers. Bioinformatic analyses of microarray data from NB tumors revealed that high ESR1 expression correlates with increased event-free survival in NB patients and favorable disease outcome. Thus, MYCN amplification may disrupt estrogen signaling sensitivity in primitive sympathetic cells through deregulation of ESR1, thereby preventing the normal induction of neuroblast differentiation. Collectively, our findings demonstrate the molecular consequences of abnormal miRNA transcription in a MYCN-driven tumor and offer unique insights into the pathology underlying MYCN-amplified NB.oncogene | embryonic development | pediatric tumor | transcription factor | hormone receptor N euroblastoma (NB) represents a remarkably heterogeneous pediatric cancer derived from precursor cells of the sympathetic ganglionic lineage, with clinical behavior ranging from spontaneous regression to rapid progression and death (1, 2). Despite the frequent display of multiple genetic defects, including chromosomal gains and losses, aneuploidy, and amplification of chromosomal material, few established molecular genetic markers associate with disease outcome. Amplification of the MYCN locus, present in ≈20 to 30% of all cases, represents the most important genetic aberration, and is strongly related to poor clinical diagnosis (3). MYCN is expressed in the migrating neural crest and encodes a phosphoprotein that belongs to the Myc network of helix-loop-helix leucine zipper transcriptional regulators, which play key roles in governing cell growth, apoptosis, and differentiation (4). Transcriptional activation is mediated by binding of the Myc/Max dimer to the consensus E-box sequence CA(C/T)GTG in target gene promoters while the mechanism of Myc-mediated transcriptional r...

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Section: Discussionsupporting

confidence: 82%

Section: Esr1 Is Repressed By Mycn-induced Mirnas and Contributes Tomentioning

confidence: 99%

MYCN-regulated microRNAs repress estrogen receptor-α ( ESR1 ) expression and neuronal differentiation in human neuroblastoma

Lovén

Zinin

Wahlström

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

124

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“…Diminished or absent ER expression has been associated tightly with methylation of a CpG island in the ER promoter in multiple cell types; Methylation of the ER gene has previously been seen in 100% of colon cancers (Issa et al, 1994), 80% of leukemias (Issa et al, 1996c), 25% of lung cancers (Issa et al, 1996a) and 25% of ER negative breast cancers (Lapidus et al, 1996). Reexpression of ER inhibits cell growth in various cancer cell lines including breast (Zajchowski et al, 1993;Jiang and Jordan, 1992), colon (Issa et al, 1994), neuroblastoma (Ma et al, 1993) and HeLa cells (Maminta et al, 1991). Our present data suggest that ER methylation (and presumed loss of expression) may play a role in the pathogenesis of GBMs as well.…”

Section: Discussionsupporting

confidence: 54%

“…ER is expressed in normal brain and its transcript has been detected in di erent types of cultured glial cells (Santagati et al, 1994). Recent studies of ER in several tumor types have indicated that this molecule may have tumor suppressor properties (Ma et al, 1993;Garcia et al, 1992). Diminished or absent ER expression has been associated tightly with methylation of a CpG island in the ER promoter in multiple cell types; Methylation of the ER gene has previously been seen in 100% of colon cancers (Issa et al, 1994), 80% of leukemias (Issa et al, 1996c), 25% of lung cancers (Issa et al, 1996a) and 25% of ER negative breast cancers (Lapidus et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

Concordant methylation of the ER and N33 genes in glioblastoma multiforme

Jedlicka

Ahuja

et al. 1998

Oncogene

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Methylation of promoter-associated CpG islands appears to be a potential way by which tumor suppressor genes are inactivated in cancer. Using Southern blot analysis, we have studied the methylation of several genes in glioblastoma multiforme (GBM), trying to determine their contribution to tumorigenesis. Genes studied included the estrogen receptor (ER), N33, the candidate tumor-suppressors P15, P16 and HIC1 and a control gene, c-abl. Hypermethylation of N33, ER, HIC1, P16, P15 and c-abl were found in 61%, 59%, 60%, 5%, 2% and 0% of GBM respectively. HIC1 methylation was detected in normal brain as well, but appeared to be more extensive in tumors. ER and N33 methylation were signi®cantly more frequent in tumors from individuals over the age of 40 (70% and 88% vs 36% and 14%). In addition, there was a strong association between ER and N33 methylation, which were concordant in 81% of the cases (P50.01). ER and N33 methylation in GBM may therefore appear as a result of shared etiologic factors, which may relate in part to aging cell populations in the brain.

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“…The data accumulated so far prove that E 2 can induce these cells to cease proliferation and to accumulate in the G 0 phase of the cell cycle, acquiring the phenotype of a mature dopaminergic neuron (Agrati et al, 1997). We also proved that several of the activities attributed to E 2 in vivo can be reproduced in our model, i.e., induction of the synthesis of specific proteins, including c-Fos, synaptophysin, and tau, or modulation of neurite growth (Ma et al, 1993;Santagati et al, 1995). We therefore believe that SK-ER3 cells represent a unique system for the study of E 2 action in neural cells.…”

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confidence: 59%

Identification of Estrogen-Responsive Genes in Neuroblastoma SK-ER3 Cells

et al. 1997

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To evaluate the role of estrogen receptor in the differentiation of cells of neural origin, we developed a molecular approach aimed at the identification of estrogen target genes by mRNA differential display PCR (ddPCR) in human neuroblastoma SK-ER3 cells. More than 3000 RNAs were examined, a few of which displayed a differential regulation pattern in response to 17␤-estradiol (E 2 ). Sequence analysis of three differentially amplified ddPCR products showed homology with the growthassociated nuclear protein prothymosin-␣ (PTMA), the Bcl2-interacting protein Nip2, and one mRNA previously described by others in fetal human brain. Two ddPCR products, referred to as P4 and P10, corresponded to new DNA sequences. Northern analysis confirmed that estrogen treatment of SK-ER3 cells resulted in the upregulation and downregulation of expression of these messages. In particular, PTMA was found to accumulate at both 1 and 17 hr after E 2 treatment, whereas P10 product accumulated only at 1 hr. Conversely, P4, Nip2, and the fetal brain-related mRNAs were significantly decreased by the treatment. Further time course analysis of PTMA and Nip2 mRNAs levels indicated that the hormone exerted a marked biphasic regulatory effect on expression of both messages during the course of cell differentiation. In the present study we report for the first time the identification of a panel of estrogen target genes in neural cells that provide new insights in the molecular mechanism of action of E 2 in cells of neural origin.

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Activated estrogen receptor mediates growth arrest and differentiation of a neuroblastoma cell line.

Cited by 75 publications

References 33 publications

MYCN-regulated microRNAs repress estrogen receptor-α ( ESR1 ) expression and neuronal differentiation in human neuroblastoma

MYCN-regulated microRNAs repress estrogen receptor-α ( ESR1 ) expression and neuronal differentiation in human neuroblastoma

Concordant methylation of the ER and N33 genes in glioblastoma multiforme

Identification of Estrogen-Responsive Genes in Neuroblastoma SK-ER3 Cells

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