Ferrand N, Stragier E, Redeuilh G et al.Glucocorticoids induce CCN5/WISP-2 expression and attenuate invasion in oestrogen receptor-negative human breast cancer cells. Biochem J 447:71-79

Biochemical Journal (Impact Factor: 4.4). 07/2012; 447(1):71-9. DOI: 10.1042/BJ20120311
Source: PubMed


CCN5 (cysteine-rich 61/connective tissue growth factor/nephroblastoma overexpressed 5)/WISP-2 [WNT1 (wingless-type MMTV integration site family, member 1)-inducible signalling pathway protein 2] is an oestrogen-regulated member of the CCN family. CCN5 is a transcriptional repressor of genes associated with the EMT (epithelial-mesenchymal transition) and plays an important role in maintenance of the differentiated phenotype in ER (oestrogen receptor)-positive breast cancer cells. In contrast, CCN5 is undetectable in more aggressive ER-negative breast cancer cells. We now report that CCN5 is induced in ER-negative breast cancer cells such as MDA-MB-231 following glucocorticoid exposure, due to interaction of the endogenous glucocorticoid receptor with a functional glucocorticoid-response element in the CCN5 gene promoter. Glucocorticoid treatment of MDA-MB-231 cells is accompanied by morphological alterations, decreased invasiveness and attenuated expression of mesenchymal markers, including vimentin, cadherin 11 and ZEB1 (zinc finger E-box binding homeobox 1). Interestingly, glucocorticoid exposure did not increase CCN5 expression in ER-positive breast cancer cells, but rather down-regulated ER expression, thereby attenuating oestrogen pathway signalling. Taken together, our results indicate that glucocorticoid treatment of ER-negative breast cancer cells induces high levels of CCN5 expression and is accompanied by the appearance of a more differentiated and less invasive epithelial phenotype. These findings propose a novel therapeutic strategy for high-risk breast cancer patients.

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    • "On the one hand, the use of GCs can induce chemoresistance in, among others, prostate and cervical cancer therapy, and through parallel down-regulation of the immune response it might facilitate metastasis [22] [23]. On the other hand, in breast cancer cells, GCs are known to indirectly repress epithelial-to-mesenchymal (EMT)-associated gene expression, eventually impacting the invasiveness of these cells [24]. The role of GCs is also contested in bladder cancer, where GCs actually increase cell proliferation and activity, but at the same time suppress the expression of multiple invasion-associated genes and also cause mesenchymal-to-epithelial transition (MET) [25]. "
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    ABSTRACT: The glucocorticoid receptor functions as a ligand-dependent transcription factor that positively or negatively regulates the transcription of various specific target genes. Not only steroidal glucocorticoids can bind and activate the glucocorticoid receptor, but also the intensively examined non-steroidal selective glucocorticoid receptor modulators can do so, albeit with a select effector profile skewed to glucocorticoid receptor transrepression. Glucocorticoids are widely used to treat inflammatory afflictions, but also as anti-cancer therapies or adjuvants thereof. As the impact of glucocorticoids and selective glucocorticoid receptor modulators has scarcely been researched in this setting, we focused on colon cancer and its stromal environment, in particular the stromal myofibroblasts, which are known to influence cancer cells via paracrine signaling.
    The Journal of Steroid Biochemistry and Molecular Biology 02/2015; 149. DOI:10.1016/j.jsbmb.2015.02.002 · 3.63 Impact Factor
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    • "In clear contrast, WISP2 is not detected in highly aggressive breast cancer cell lines such as MDAMB231 [13], [14] and importantly, ectopic expression of WISP2 in this cell line was accompanied by attenuation of the proliferative and invasive phenotype [13]. Similar findings were obtained when WISP2 was transcriptionally upregulated by glucocorticoids in the same cellular model [15]. In concordance with the cellular findings, the clinical data show that WISP2 expression is principally detected in preneoplastic disorders such as non-invasive ductal carcinoma in situ (DCIS) and atypical ductal hyperplasia, whereas WISP2 expression levels were either minimal or undetectable in invasive breast tumors [11], [16]. "
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    ABSTRACT: It has been proposed that the epithelial-mesenchymal transition (EMT) in mammary epithelial cells and breast cancer cells generates stem cell features. WISP2 (Wnt-1-induced signaling protein-2) plays an important role in maintenance of the differentiated phenotype of estrogen receptor-positive breast cancer cells and loss of WISP2 is associated with EMT. We now report that loss of WISP2 in MCF7 breast cancer cells can also promote the emergence of a cancer stem-like cell phenotype characterized by high expression of CD44, increased aldehyde dehydrogenase activity and mammosphere formation. Higher levels of the stem cell markers Nanog and Oct3/4 were observed in those mammospheres. In addition we show that low-cell inoculums are capable of tumor formation in the mammary fat pad of immunodeficient mice. Gene expression analysis show an enrichment of markers linked to stem cell function such as SOX9 and IGFBP7 which is linked to TGF-β inducible, SMAD3-dependent transcription. Taken together, our data demonstrate that WISP2 loss promotes both EMT and the stem-like cell phenotype.
    PLoS ONE 02/2014; 9(2):e87878. DOI:10.1371/journal.pone.0087878 · 3.23 Impact Factor
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    • "No differential expression of the studied genes was observed between normal pituitaries and each different subtype of pituitary adenomas, except for over-expression of WISP2 in ACTH-secreting pituitary tumor. WISP2, a tumor suppressor gene involved in attenuating tumor invasion [35], [36], has a glucocorticoid-responsive region in its promoter [37]. The elevated glucocorticoid levels observed in ACTH-secreting pituitary tumors would, therefore, over activate the WISP2 transcription. "
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    ABSTRACT: Canonical and non-canonical Wnt pathways are involved in the genesis of multiple tumors; however, their role in pituitary tumorigenesis is mostly unknown. This study evaluated gene and protein expression of Wnt pathways in pituitary tumors and whether these expression correlate to clinical outcome. GENES OF THE WNT CANONICAL PATHWAY: activating ligands (WNT11, WNT4, WNT5A), binding inhibitors (DKK3, sFRP1), β-catenin (CTNNB1), β-catenin degradation complex (APC, AXIN1, GSK3β), inhibitor of β-catenin degradation complex (AKT1), sequester of β-catenin (CDH1), pathway effectors (TCF7, MAPK8, NFAT5), pathway mediators (DVL-1, DVL-2, DVL-3, PRICKLE, VANGL1), target genes (MYB, MYC, WISP2, SPRY1, TP53, CCND1); calcium dependent pathway (PLCB1, CAMK2A, PRKCA, CHP); and planar cell polarity pathway (PTK7, DAAM1, RHOA) were evaluated by QPCR, in 19 GH-, 18 ACTH-secreting, 21 non-secreting (NS) pituitary tumors, and 5 normal pituitaries. Also, the main effectors of canonical (β-catenin), planar cell polarity (JNK), and calcium dependent (NFAT5) Wnt pathways were evaluated by immunohistochemistry. There are no differences in gene expression of canonical and non-canonical Wnt pathways between all studied subtypes of pituitary tumors and normal pituitaries, except for WISP2, which was over-expressed in ACTH-secreting tumors compared to normal pituitaries (4.8x; p = 0.02), NS pituitary tumors (7.7x; p = 0.004) and GH-secreting tumors (5.0x; p = 0.05). β-catenin, NFAT5 and JNK proteins showed no expression in normal pituitaries and in any of the pituitary tumor subtypes. Furthermore, no association of the studied gene or protein expression was observed with tumor size, recurrence, and progressive disease. The hierarchical clustering showed a regular pattern of genes of the canonical and non-canonical Wnt pathways randomly distributed throughout the dendrogram. Our data reinforce previous reports suggesting no activation of canonical Wnt pathway in pituitary tumorigenesis. Moreover, we describe, for the first time, evidence that non-canonical Wnt pathways are also not mis-expressed in the pituitary tumors.
    PLoS ONE 04/2013; 8(4):e62424. DOI:10.1371/journal.pone.0062424 · 3.23 Impact Factor
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