Molecular cloning and characterization of the human WISP-2/CCN5 gene promoter reveal its upregulation by oestrogens

Fritah, Asmaà; Redeuilh, Gérard; Sabbah, Michèle

doi:10.1677/joe.1.07009

Cited by 29 publications

(46 citation statements)

References 47 publications

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“…However, their effect in terms of offering new concepts of the molecular network of human breast cancer development, diagnostics, or therapeutic modalities remains limited. Over the last several years, after the identification of CCN5 in noninvasive human breast tumor cells and samples by using RNA differential display analysis (14), CCN5 has been implicated as having an important role in human breast disease and other cancers as well (9,10,14,20,(29)(30)(31)(32)(33). The present immunohistochemical and in situ hybridization analysis studies have shown a differential expression profile of CCN5 in human breast samples.…”

Section: Discussionmentioning

confidence: 57%

CCN5/WISP-2 Expression in Breast Adenocarcinoma Is Associated with Less Frequent Progression of the Disease and Suppresses the Invasive Phenotypes of Tumor Cells

et al. 2008

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Although previous in vitro studies predicted that CCN5/ WISP-2 may act as an anti-invasive gene in breast cancer, the distribution pattern of CCN5 in breast cancer samples is conflicting. Thus, we systematically investigated the CCN5 expression profile in noninvasive and invasive breast tumor samples and its functional relevance in breast cancer progression. The studies showed that CCN5 expression is biphasic, such that in normal samples CCN5 expression is undetectable, whereas its expression is markedly increased in noninvasive breast lesions, including atypical ductal hyperplasia and ductal carcinoma in situ. Further, CCN5 mRNA and protein levels are significantly reduced as the cancer progresses from a noninvasive to invasive type. Additionally, we showed that CCN5 mRNA and protein level was almost undetectable in poorly differentiated cancers compared with the moderately or well-differentiated samples and its expression inversely correlated with lymph node positivity. The result was further supported by evaluating the RNA expression profile in microdissected sections using real-time PCR analysis. Therefore, our data suggest a protective function of CCN5 in noninvasive breast tumor cells. This hypothesis was further supported by our in vitro studies illuminating that CCN5 is a negative regulator of migration and invasion of breast cancer cells, and these events could be regulated by CCN5 through the modulation of the expression of genes essential for an invasive front. These include Snail-E-cadherin signaling and matrix metalloproteinase (MMP)-9 and MMP-2. Collectively, these studies suggest that the protective effect of CCN5 in breast cancer progression may have important therapeutic implications. [Cancer Res 2008;68(18):7606-12]

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Section: Discussionmentioning

confidence: 57%

CCN5/WISP-2 Expression in Breast Adenocarcinoma Is Associated with Less Frequent Progression of the Disease and Suppresses the Invasive Phenotypes of Tumor Cells

et al. 2008

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“…Several studies have shown that nucleotide alterations from the core sequence on each side of an ERE palindrome, results in a significant decrease in ER-binding affinity and transcriptional activation (Klinge 2001). This lack of sequence identity with a canonical ERE does not preclude direct ligand-activated ER regulation as demonstrated for the imperfect ERE present in the proximal promoter of the human WISP2 gene (5 0 -GGTCA-CAC-CCACC-3 0 ) (Fritah et al 2006). Therefore, we directly tested the hormone inducibility of the STC2 proximal promoter region; however, E 2 , RA or P4 treatments did not induce the STC2 promoter.…”

Section: Transcriptional Regulation Of Stc2 Expression By Oestrogen Amentioning

confidence: 99%

Stanniocalcin 2 expression is regulated by hormone signalling and negatively affects breast cancer cell viability in vitro

Raulic

Ramos-Valdes

DiMattia

2008

Journal of Endocrinology

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Stanniocalcin 1 (STC1) and STC2 are secreted, homodimeric glycoproteins that share 30% amino acid sequence identity. Breast tumour gene profiling studies have demonstrated significantly upregulated STC2 expression in hormoneresponsive positive breast tumours; therefore, the purpose of this study was to investigate STC2 hormonal regulation and function in breast cancer cells. Here we report that STC2 is expressed in a number of human breast cancer cell lines, regardless of their oestrogen (E 2 ) and progesterone (P4) receptor status, and its expression is readily detectable in human and mouse mammary gland tumours. Besides E 2 , retinoic acid (RA) and P4 play an important role in the regulation of STC2 expression, not only in MCF-7 but also in other breast cancer and non-breast cell lines. The expression of the related hormone, STC1, is not affected by the above hormones in breast and endometrial cancer cell lines implying a fundamental difference in regulation in cancer cell lines. The induction of STC2 expression by E 2 and RA occurs at the transcriptional level but through intermediary transcription factors. The STC2 proximal promoter region is not responsible for hormonal induction, but exhibits a high basal transcriptional activity. Constitutive STC2 expression in human breast cancer cell lines resulted in significant impairment of cell growth, migration and cell viability after serum withdrawal. In conclusion, STC2 is a downstream target of E 2 , P4 and RA signalling pathways. In hormone receptor negative cell lines it can function in a paracrine/autocrine fashion to reduce cell proliferation.

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“…*, P < 0.01 versus controls. B, schematic representation of the minimal hCCN5 promoter that was recently cloned and characterized (49). Estrogen response element is shown as ERE motif here.…”

Section: Disclosure Of Potential Conflicts Of Interestmentioning

confidence: 99%

Gain of Oncogenic Function of p53 Mutants Induces Invasive Phenotypes in Human Breast Cancer Cells by Silencing CCN5/WISP-2

et al. 2008

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CCN5/WISP-2 is overexpressed in noninvasive breast cancer cells and tissue samples, whereas its expression is minimal or undetected in invasive conditions. CCN5/WISP-2 has been considered as an antiinvasive gene because CCN5/WISP-2 silencing augments the invasive phenotypes in vitro. However, the mechanism of silencing of CCN5 during the progression of the disease has been elusive. Because p53 mutations are associated with breast cancer progression and have been shown to correlate inversely with CCN5/WISP-2 expression in other cancer cell types, the objective of this study was to explore whether p53 mutants suppress CCN5 expression in breast tumor cells resulting in the progression of this disease. We found CCN5 expression is inversely correlated with the mutational activation of p53 in human breast tumor cells. The ectopic expression of p53 mutants in ER-positive noninvasive breast tumor cells silenced the CCN5/WISP-2 expression and enhanced invasive phenotypes, including the induction of morphologic changes from the epithelial-to-mesenchymal type along with the alterations of hallmark proteins of these cell types and an augmentation of the migration of these cells. The suppression of CCN5 by the p53 mutants can be nullified by estrogen signaling in these cells through the transcriptional activation of the CCN5 gene. Moreover, the invasive changes can be imitated by blocking the CCN5/WISP-2 expression through RNA interference or can be reversed by the addition of CCN5/WISP-2 recombinant protein in the culture. Thus, these studies suggest that CCN5 inactivation could be an essential molecular event for p53 mutant-induced invasive phenotypes. [Cancer Res 2008;68(12):4580-7]

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Molecular cloning and characterization of the human WISP-2/CCN5 gene promoter reveal its upregulation by oestrogens

Cited by 29 publications

References 47 publications

CCN5/WISP-2 Expression in Breast Adenocarcinoma Is Associated with Less Frequent Progression of the Disease and Suppresses the Invasive Phenotypes of Tumor Cells

CCN5/WISP-2 Expression in Breast Adenocarcinoma Is Associated with Less Frequent Progression of the Disease and Suppresses the Invasive Phenotypes of Tumor Cells

Stanniocalcin 2 expression is regulated by hormone signalling and negatively affects breast cancer cell viability in vitro

Gain of Oncogenic Function of p53 Mutants Induces Invasive Phenotypes in Human Breast Cancer Cells by Silencing CCN5/WISP-2

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