Role of WISP-2/CCN5 in the Maintenance of a Differentiated and Noninvasive Phenotype in Human Breast Cancer Cells

Abstract

WISP-2/CCN5 is an estrogen-regulated member of the "connective tissue growth factor/cysteine-rich 61/ nephroblastoma overexpressed" (CCN) family of the cell growth and differentiation regulators. The WISP-2/ CCN5 mRNA transcript is undetectable in normal human mammary cells, as well as in highly aggressive breast cancer cell lines, in contrast with its higher level in the breast cancer cell lines characterized by a more differentiated phenotype. We report here that knockdown of WISP-2/CCN5 by RNA interference in estrogen receptor alpha (ER␣)-positive MCF-7 breast cancer cells induced an estradiol-independent growth linked to a loss of ER␣ expression and promoted epithelial-to-mesenchymal transdifferentiation. In contrast, forced expression of WISP-2/CCN5 directed MCF-7 cells toward a more differentiated phenotype. When introduced into the poorly differentiated, estrogen-independent, and invasive MDA-MB-231 breast cancer cells, WISP-2/ CCN5 was able to reduce their proliferative and invasive phenotypes. In a series of ER␣-positive tumor biopsies, we found a positive correlation between the expression of WISP-2/CCN5 and ID2, a transcriptional regulator of differentiation in normal and transformed breast cells. We propose that WISP-2/CCN5 is an important regulator involved in the maintenance of a differentiated phenotype in breast tumor epithelial cells and may play a role in tumor cell invasion and metastasis.

Non-canonical HIF-2α function drives autonomous breast cancer cell growth via an AREG–EGFR/ErbB4 autocrine loop

“…To the best of our knowledge, AREG establishes the first direct link between HIF-2a-dependent transcription and EGFR family activation in human breast cancers. Moreover, we found a strong correlation of HIF-2a, AREG and WISP2 protein levels in tumor samples with luminal differentiation, providing evidence that the HIF-2a-specific transcriptional pathway could have an important role in maintaining a noninvasive phenotype, as it has been reported for tumors expressing WISP2 before (Banerjee et al, 2008;Fritah et al, 2008).…”

The Novel Secreted Adipokine WNT1-inducible Signaling Pathway Protein 2 (WISP2) Is a Mesenchymal Cell Activator of Canonical WNT

“…Interestingly, Wisp2 expression was very low in these cells (C T values, 36 -40) which are under high endogenous WNT/␤-catenin activation. In contrast, the breast tumor cells MCF7 had a high Wisp2 expression (C T values, 26 -27) as also reported previously (24). However, these cells were cloned from the pleural effusion of a patient with breast cancer, and their origin is uncertain.…”

CCN5/WISP-2: A micromanager of breast cancer progression

“…4). In contrast, induced expression of CCN5 or supplementation of CCN5 protein in CCN5 (-) invasive cancer cells reduces the rate of proliferation, migration and invasion (Fritah et al 2008;Banerjee et al 2008). Collectively, the contrasting pathobiological roles (i.e., their participation in steroids and growth factorsinduced proliferation and their protection of cells from EMT, migration and invasion) of CCN5 under different microenvironments suggest that CCN5 may be a two-faced cancer gene, and the major role of CCN5, at least under culture conditions, is to protect the cells from gaining invasive phenotypes.…”

“…For example, silencing of CCN5 in MCF-7 non-invasive carcinoma cells by CCN5-specific shRNA significantly enhances motility and EMT, and it modulates the expression of some genes associated with invasive phenotypes of cancer cells Dhar et al 2008;Fritah et al 2008). In CCN5 knockout ER-α positive breast cancer cells, IGF-1 and EGF lost their mitogenic effect Dhar et al 2007b), but possibly gained aggressive phenotypes (i.e., Fig.…”