Glucocorticoids induce CCN5/WISP-2 expression and attenuate invasion in oestrogen receptor-negative human breast cancer cells

Abstract

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.

Loss of WISP2/CCN5 in Estrogen-Dependent MCF7 Human Breast Cancer Cells Promotes a Stem-Like Cell Phenotype

“…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].…”

Components of the Canonical and Non-Canonical Wnt Pathways Are Not Mis-Expressed in Pituitary Tumors

“…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.…”

The CCN family acting throughout the body: recent research developments

“…TGF-β is attracting the interest of medical scientists also as a mediator of the epithelial-mesenchymal transition (EMT), enhancing CCN1, CCN2, and CCN4 expression, while repressing CCN3 expression (39,40). As another multiple CCN regulator, glucocorticoids enhance the gene expression of CCN1, CCN2, and CCN5 (39,41). However, in mice, the induction of CCN2 by dexamethasone is strain dependent (42), and CCN5 induction in humans has been confirmed, so far, only in estrogen receptor (ER)-negative breast cancer cells.…”