Elsevier

Neoplasia

Volume 6, Issue 2, March–April 2004, Pages 179-185
Neoplasia

WISP3 (CCN6) Is a Secreted Tumor-Suppressor Protein that Modulates IGF Signaling in Inflammatory Breast Cancer1

https://doi.org/10.1593/neo.03316Get rights and content
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open access

Abstract

Inflammatory breast cancer (IBC) is the most lethal form of locally advanced breast cancer. We have found that WISP3 is lost in 80% of human IBC tumors and that it has growth- and angiogenesis-inhibitory functions in breast cancer in vitro and in vivo. WISP3 is a cysteine-rich, putatively secreted protein that belongs to the CCN family. It contains a signal peptide at the N-terminus and four highly conserved motifs. Here, for the first time, we investigate the function of WISP3 protein in relationship to its structural features. We found that WISP3 is secreted into the conditioned media and into the lumens of normal breast ducts. Once secreted, WISP3 was able to decrease, directly or through induction of other molecule(s), the IGF-1-induced activation of the IGF-IR, and two of its main downstream signaling molecules, IRS1 and ERK-1/2, in SUM149 IBC cells. Furthermore, WISP3 containing conditioned media decreased the growth rate of SUM149 cells. This work sheds light into the mechanism of WISP3 function by demonstrating that it is secreted and that, once in the extracellular media, it induces a series of molecular events that leads to modulation of IGF-IR signaling pathways and cellular growth in IBC cells.

Keywords

IGF-binding proteins
MAPK signaling
cell proliferation
cell cycle control
ERK-1/2 phosphorylation

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1

This work was supported, in part, by Army grants DAMD17-02-1-0490 (C.G.K.), DAMD1702-1-491 (C.G.K.), and DAMD-17-00-1-0345 (S.D.M.); National Institutes of Health grants K08CAO9O876 (C.G.K.), RO1CA77612 (S.D.M.) and 1 P50-CADE97258 (S.D.M.); and a grant from the John and Suzanne Munn Endowed Research Fund of the University of Michigan Comprehensive Cancer Center (C.G.K.).