H19 Overexpression in Breast Adenocarcinoma Stromal Cells Is Associated with Tumor Values and Steroid Receptor Status but Independent of p53 and Ki-67 Expression

Adriaenssens, Éric; Dumont, Lionel; Lottin, Séverine; Bolle, Domitille; Leprêtre, Alain; Delobelle, A; Bouali, Fatima; Dugimont, Thierry; Cottet, J; Curgy, Jean-Jacques

doi:10.1016/s0002-9440(10)65748-3

Cited by 114 publications

(101 citation statements)

References 90 publications

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“…At birth, the H19 RNA synthesis is strongly attenuated and although this repression is general, its rate depends on the organ. This repression is not complete in the mammary cord ( Figure 1) and a basal transcription level persists in the adult, as previously described (Douc-Rasy et al, 1993;Dugimont et al, 1995;Adriaenssens et al, 1998). This pattern of expression remains all along the prepubertal development and during this stage the mammary gland growth is isometric and no morphological or functional variations occur.…”

Section: Discussionsupporting

confidence: 75%

“…H19 is expressed in most fetal tissues, except in the thymus, and is repressed in almost all adult organs except the cardiac and skeletal muscles Leibovitch et al, 1991), the uterus (Ariel et al, 1997b), to a lesser extent the kidney, the adrenal glands, the lung (Zhang and Tycko, 1992) and the mammary gland, where a basal but signi®cant expression has been detected (Douc-Rasy et al, 1993;Dugimont et al, 1995;Adriaenssens et al, 1998). This pattern of expression suggests that H19 could be implicated in fetal development.…”

Section: Introductionmentioning

confidence: 98%

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Steroid hormones modulate H19 gene expression in both mammary gland and uterus

et al. 1999

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H19 is an imprinted and developmentally regulated gene whose product remains apparently untranslated. In a previous study on breast adenocarcinomas, we reported that overexpression of the H19 gene was signi®cantly correlated with the presence of steroid receptors, suggesting the putative role of hormones in H19 transcription. To determine the mode of steroid action, we have detected levels of H19 RNA synthesis during mammary gland development by in situ hybridization (ISH): two peaks of H19 transcription occur during puberty and pregnancy. Furthermore, we demonstrated by ISH that in the uterus H19 RNA synthesis is high during estrus and metestrus phases. To test steroid control of H19 transcription, ovariectomized and adrenalectomized mice were supplemented, 1 week after surgery, with 17-b-estradiol (E2, 20 mg/kg/day), progesterone (P, 1 mg/kg/day) or corticosterone (B, 0.3 mg/ kg/day) for 2 weeks. According to ISH data, E2 and to a lesser extent B stimulated H19 transcription in the uterus, whereas P inhibited it. To con®rm the in vivo results, in vitro experiments were performed using cultures of MCF-7 cells (a hormone-sensitive mammary cell line). E2 stimulated the endogenous H19 gene of this cell line and tamoxifen inhibited this e ect. Furthermore, we performed transient cotransfections in MCF-7, in HBL-100 (another hormone-sensitive mammary cell line) and in BT-20 (a hormone-insensitive mammary cell line) with various constructs of ERa (WT or mutated) and PR-A, in presence or absence of steroid hormones. We demonstrated that ERa up-regulated the H19 promoter in MCF-7 and in HBL-100, whereas PR-A did not have any e ect per se. Moreover, in MCF-7, PR-A antagonized clearly the ERa-mediated promoter enhancement, but in HBL-100 this counteracting e ect on the ERa up-regulation was not found. Interestingly, the same experiments performed in BT-20 cell line provided very similar results as those obtained in MCF-7 cells, with a clear down-regulation mediated by PR-A on the H19 promoter. All these in vitro data are in agreement with in vivo results. In addition, data obtained with ERa mutants indicate that H19 promoter activation is both ligand-dependent and ligand-independent. We have thus demonstrated that H19 gene expression is controlled by steroid hormones; furthermore, this gene is highly expressed in hormone-sensitive organs when the hormonal stimulation is accompanied with a morphological repair.

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Section: Discussionsupporting

confidence: 75%

Section: Introductionmentioning

confidence: 98%

Steroid hormones modulate H19 gene expression in both mammary gland and uterus

et al. 1999

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“…These cases have been extensively characterized and reported (Adriaenssens et al, 1998). Noncancerous mammary gland biopsies provided from mammoplasty material were obtained from the Department of Plastic Surgery (Professor Pellerin) of the Medical University of Lille (France).…”

Section: Immunocytochemistry and Immunohistochemistrymentioning

confidence: 99%

Nerve growth factor overexpression and autocrine loop in breast cancer cells

et al. 2003

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We show here that nerve growth factor (NGF), the canonical neurotrophic factor, is synthesized and released by breast cancer cells. High levels of NGF transcript and protein were detected in breast cancer cells by reverse transcription-PCR, Western blotting, ELISA assay and immunohistochemistry. Conversely, NGF production could not be detected in normal breast epithelial cells at either the transcriptional or protein level. Confocal analysis indicated the presence of NGF within classical secretion vesicles. Breast cancer cell-produced NGF was biologically active, as demonstrated by its ability to induce the neuronal differentiation of embryonic neural precursor cells. Importantly, the constitutive growth of breast cancer cells was strongly inhibited by either NGF-neutralizing antibodies or K-252a, a pharmacological inhibitor of NGF receptor TrkA, indicating the existence of an NGF autocrine loop. Together, our data demonstrate the physiological relevance of NGF in breast cancer and its potential interest as a marker and therapeutic target.

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“…H19 was first described as a tumor suppressor (18,19), but more recent analysis shows that H19 expression is reactivated in breast (20), endometrial (21), lung (22), cervical (23), esophageal (24), and bladder (25) tumors. The H19/insulin-like growth factor 2 (IGF2) locus, containing both the H19 and IGF2 genes, is subject to genomic imprinting, which leads to differential allelic expression of H19 from the maternal allele and IGF2 from the paternal allele (26).…”

Section: Introductionmentioning

confidence: 99%

The c-Myc Oncogene Directly Induces the H19 Noncoding RNA by Allele-Specific Binding to Potentiate Tumorigenesis

et al. 2006

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The product of the MYC oncogene is widely deregulated in cancer and functions as a regulator of gene transcription. Despite an extensive profile of regulated genes, the transcriptional targets of c-Myc essential for transformation remain unclear. In this study, we show that c-Myc significantly induces the expression of the H19 noncoding RNA in diverse cell types, including breast epithelial, glioblastoma, and fibroblast cells. c-Myc binds to evolutionarily conserved E-boxes near the imprinting control region to facilitate histone acetylation and transcriptional initiation of the H19 promoter. In addition, c-Myc down-regulates the expression of insulin-like growth factor 2 (IGF2), the reciprocally imprinted gene at the H19/ IGF2 locus. We show that c-Myc regulates these two genes independently and does not affect H19 imprinting. Indeed, allele-specific chromatin immunoprecipitation and expression analyses indicate that c-Myc binds and drives the expression of only the maternal H19 allele. The role of H19 in transformation is addressed using a knockdown approach and shows that down-regulation of H19 significantly decreases breast and lung cancer cell clonogenicity and anchorage-independent growth. In addition, c-Myc and H19 expression shows strong association in primary breast and lung carcinomas. This work indicates that c-Myc induction of the H19 gene product holds an important role in transformation. (Cancer Res 2006; 66(10): 5330-7)

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H19 Overexpression in Breast Adenocarcinoma Stromal Cells Is Associated with Tumor Values and Steroid Receptor Status but Independent of p53 and Ki-67 Expression

Abstract: In a previous study we described the expression of the H19 gene by in situ hybridization (

Cited by 114 publications

References 90 publications

Steroid hormones modulate H19 gene expression in both mammary gland and uterus

Steroid hormones modulate H19 gene expression in both mammary gland and uterus

Nerve growth factor overexpression and autocrine loop in breast cancer cells

The c-Myc Oncogene Directly Induces the H19 Noncoding RNA by Allele-Specific Binding to Potentiate Tumorigenesis

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