Abstract
The cysteine-rich protein CCN6 [or Wnt-1-induced signaling protein 3 (WISP3)] exerts tumor-suppressive effects in aggressive inflammatory breast cancer. Loss of CCN6 is associated with poorly differentiated phenotypes and increased invasion. Here, we show that reduction of CCN6 expression occurs in 60% of invasive breast carcinomas and is associated with axillary lymph node metastases. Furthermore, low CCN6 expression in invasive carcinoma tissue samples correlates with reduced expression of E-cadherin. In vitro, RNA interference knockdown of CCN6 in two benign human mammary epithelial cell lines (HME and MCF10A) decreased expression of E-cadherin protein and mRNA and reduced activity of the E-cadherin promoter; this reduction was dependent on intact E-box elements. CCN6 knockdown in HME cells resulted in up-regulation of the E-cadherin transcriptional repressors Snail and ZEB1 and enhanced their recruitment and binding to the E-cadherin promoter as analyzed by chromatin immunoprecipitation assays. Small interfering RNA-mediated knockdown of ZEB1 or Snail blocked the down-regulation of E-cadherin caused by CCN6 inhibition. These data show, for the first time, that CCN6 expression is reduced or lost in a substantial number of invasive breast carcinomas and that CCN6 modulates transcriptional repressors of E-cadherin. Together, our results lead to a new hypothesis that Snail and ZEB1 are downstream of CCN6 and play a critical role in CCN6-mediated regulation of E-cadherin in breast cancer.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 893-904 |
| Number of pages | 12 |
| Journal | American Journal of Pathology |
| Volume | 172 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 2008 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Pathology and Forensic Medicine
Cite this
Inhibition of CCN6 (Wnt-1-induced signaling protein 3) down-regulates E-cadherin in the breast epithelium through induction of snail and ZEB1. / Huang, Wei; Zhang, Yanhong; Varambally, Sooryanarayana; Chinnaiyan, Arul M.; Banerjee, Mousumi; Merajver, Sofia D.; Kleer, Celina G.
In: American Journal of Pathology, Vol. 172, No. 4, 04.2008, p. 893-904.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Inhibition of CCN6 (Wnt-1-induced signaling protein 3) down-regulates E-cadherin in the breast epithelium through induction of snail and ZEB1
AU - Huang, Wei
AU - Zhang, Yanhong
AU - Varambally, Sooryanarayana
AU - Chinnaiyan, Arul M.
AU - Banerjee, Mousumi
AU - Merajver, Sofia D.
AU - Kleer, Celina G.
PY - 2008/4
Y1 - 2008/4
N2 - The cysteine-rich protein CCN6 [or Wnt-1-induced signaling protein 3 (WISP3)] exerts tumor-suppressive effects in aggressive inflammatory breast cancer. Loss of CCN6 is associated with poorly differentiated phenotypes and increased invasion. Here, we show that reduction of CCN6 expression occurs in 60% of invasive breast carcinomas and is associated with axillary lymph node metastases. Furthermore, low CCN6 expression in invasive carcinoma tissue samples correlates with reduced expression of E-cadherin. In vitro, RNA interference knockdown of CCN6 in two benign human mammary epithelial cell lines (HME and MCF10A) decreased expression of E-cadherin protein and mRNA and reduced activity of the E-cadherin promoter; this reduction was dependent on intact E-box elements. CCN6 knockdown in HME cells resulted in up-regulation of the E-cadherin transcriptional repressors Snail and ZEB1 and enhanced their recruitment and binding to the E-cadherin promoter as analyzed by chromatin immunoprecipitation assays. Small interfering RNA-mediated knockdown of ZEB1 or Snail blocked the down-regulation of E-cadherin caused by CCN6 inhibition. These data show, for the first time, that CCN6 expression is reduced or lost in a substantial number of invasive breast carcinomas and that CCN6 modulates transcriptional repressors of E-cadherin. Together, our results lead to a new hypothesis that Snail and ZEB1 are downstream of CCN6 and play a critical role in CCN6-mediated regulation of E-cadherin in breast cancer.
AB - The cysteine-rich protein CCN6 [or Wnt-1-induced signaling protein 3 (WISP3)] exerts tumor-suppressive effects in aggressive inflammatory breast cancer. Loss of CCN6 is associated with poorly differentiated phenotypes and increased invasion. Here, we show that reduction of CCN6 expression occurs in 60% of invasive breast carcinomas and is associated with axillary lymph node metastases. Furthermore, low CCN6 expression in invasive carcinoma tissue samples correlates with reduced expression of E-cadherin. In vitro, RNA interference knockdown of CCN6 in two benign human mammary epithelial cell lines (HME and MCF10A) decreased expression of E-cadherin protein and mRNA and reduced activity of the E-cadherin promoter; this reduction was dependent on intact E-box elements. CCN6 knockdown in HME cells resulted in up-regulation of the E-cadherin transcriptional repressors Snail and ZEB1 and enhanced their recruitment and binding to the E-cadherin promoter as analyzed by chromatin immunoprecipitation assays. Small interfering RNA-mediated knockdown of ZEB1 or Snail blocked the down-regulation of E-cadherin caused by CCN6 inhibition. These data show, for the first time, that CCN6 expression is reduced or lost in a substantial number of invasive breast carcinomas and that CCN6 modulates transcriptional repressors of E-cadherin. Together, our results lead to a new hypothesis that Snail and ZEB1 are downstream of CCN6 and play a critical role in CCN6-mediated regulation of E-cadherin in breast cancer.
UR - http://www.scopus.com/inward/record.url?scp=42049085877&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=42049085877&partnerID=8YFLogxK
U2 - 10.2353/ajpath.2008.070899
DO - 10.2353/ajpath.2008.070899
M3 - Article
C2 - 18321996
AN - SCOPUS:42049085877
VL - 172
SP - 893
EP - 904
JO - American Journal of Pathology
JF - American Journal of Pathology
SN - 0002-9440
IS - 4
ER -