Research Papers:

The matricellular protein CCN6 (WISP3) decreases Notch1 and suppresses breast cancer initiating cells

Wei Huang, Emily E. Martin, Boris Burman, Maria E. Gonzalez and Celina G. Kleer _

PDF  |  HTML  |  Supplementary Files  |  How to cite

Oncotarget. 2016; 7:25180-25193. https://doi.org/10.18632/oncotarget.7734

Metrics: PDF 2041 views  |   HTML 2403 views  |   ?  


Wei Huang1, Emily E. Martin1, Boris Burman1, Maria E. Gonzalez1 and Celina G. Kleer1

1 Department of Pathology and Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA

Correspondence to:

Celina G. Kleer, email:

Keywords: breast cancer, triple negative, CCN6, WISP3, epithelial to mesenchymal transition

Received: December 15, 2015 Accepted: February 08, 2016 Published: February 25, 2016


Increasing evidence supports that the epithelial to mesenchymal transition (EMT) in breast cancer cells generates tumor initiating cells (TICs) but the contribution of the tumor microenvironment to these programs needs further elucidation. CCN6 (WISP3) is a secreted matrix-associated protein (36.9 kDa) of the CCN family (named after CTGF, Cyr61 and Nov) that is reduced or lost in invasive carcinomas of the breast with lymph node metastasis and in inflammatory breast cancer. CCN6 exerts breast cancer growth and invasion inhibitory functions, but the mechanisms remain to be defined. In the present study we discovered that ectopic CCN6 overexpression in triple negative (TN) breast cancer cells and in cells derived from patients is sufficient to induce a mesenchymal to epithelial transition (MET) and to reduce TICs. In vivo, CCN6 overexpression in the TIC population of MDA-MB-231 cells delayed tumor initiation, reduced tumor volume, and inhibited the development of metastasis. Our studies reveal a novel CCN6/Slug signaling axis that regulates Notch1 signaling activation, epithelial cell phenotype and breast TICs, which requires the conserved thrombospondin type 1 (TSP1) motif of CCN6. The relevance of these data to human breast cancer is highlighted by the finding that CCN6 protein levels are inversely correlated with Notch1 intracellular activated form (NICD1) in 69.5% of invasive breast carcinomas. These results demonstrate that CCN6 regulates epithelial and mesenchymal states transition and TIC programs, and pinpoint one responsible mechanism.

Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 7734