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Originally published online as doi:10.2353/ajpath.2008.070899 on March 5, 2008

Published online before print March 5, 2008
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(American Journal of Pathology. 2008;172:893-904.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.070899

Inhibition of CCN6 (Wnt-1-Induced Signaling Protein 3) Down-Regulates E-Cadherin in the Breast Epithelium through Induction of Snail and ZEB1

Wei Huang*, Yanhong Zhang*, Sooryanarayana Varambally*{dagger}, Arul M. Chinnaiyan*{dagger}, Mousumi Banerjee{ddagger}, Sofia D. Merajver{dagger}§ and Celina G. Kleer*{dagger}

From the Departments of Pathology,* Biostatistics,{ddagger} and Internal Medicine,§ Division of Hematology/Oncology, and the Comprehensive Cancer Center,{dagger} University of Michigan Medical Center, Ann Arbor, Michigan

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.






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Copyright © 2008 by the American Society for Investigative Pathology.