Role of WISP-2/CCN5 in the maintenance of a differentiated and noninvasive phenotype in human breast cancer cells.
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 (ERalpha)-positive MCF-7 breast cancer cells induced an estradiol-independent growth linked to a loss of ERalpha 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 ERalpha-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.
Fritah
Asmaà
A
INSERM 673, Hôpital Saint-Antoine, 184 Rue du Faubourg Saint-Antoine, 75571 Paris cedex 12, France.
Saucier
Cécile
C
De Wever
Olivier
O
Bracke
Marc
M
Bièche
Ivan
I
Lidereau
Rosette
R
Gespach
Christian
C
Drouot
Sylvain
S
Redeuilh
Gérard
G
Sabbah
Michèle
M
D001943:Breast Neoplasms / Q000209:etiology / Q000473:pathology*; D055511:CCN Intercellular Signaling Proteins; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D047628:Estrogen Receptor alpha; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010641:Phenotype; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D012097:Repressor Proteins; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
D055511:CCN Intercellular Signaling Proteins; C413323:CCN5 protein, human; D047628:Estrogen Receptor alpha; D036341:Intercellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D014157:Transcription Factors