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Journal of Cancer Research and Clinical Oncology

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01-12-2018 | Original Article – Cancer Research

Signaling network involved in the GPC3-induced inhibition of breast cancer progression: role of canonical Wnt pathway

Authors: Dolores Fernández, Macarena Guereño, María Amparo Lago Huvelle, Magalí Cercato, María Giselle Peters

Published in: Journal of Cancer Research and Clinical Oncology | Issue 12/2018

Abstract

Purpose

We have shown that GPC3 overexpression in breast cancer cells inhibits in vivo tumor progression, by acting as a metastatic suppressor. GPC3-overexpressing cells are less clonogenic, viable and motile, while their homotypic adhesion is increased. We have presented evidences indicating that GPC3 inhibits canonical Wnt and Akt pathways, while non-canonical Wnt and p38MAPK cascades are activated. In this study, we aimed to investigate whether GPC3-induced Wnt signaling inhibition modulates breast cancer cell properties as well as to describe the interactions among pathways modulated by GPC3.

Methods

Fluorescence microscopy, qRT-PCR microarray, gene reporter assay and Western blotting were performed to determine gene expression levels, signaling pathway activities and molecule localization. Lithium was employed to activate canonical Wnt pathway and treated LM3-GPC3 cell viability, migration, cytoskeleton organization and homotypic adhesion were assessed using MTS, wound healing, phalloidin staining and suspension growth assays, respectively.

Results

We provide new data demonstrating that GPC3 blocks—also at a transcriptional level—both autocrine and paracrine canonical Wnt activities, and that this inhibition is required for GPC3 to modulate migration and homotypic adhesion. Our results indicate that GPC3 is secreted into the extracellular media, suggesting that secreted GPC3 competes with Wnt factors or interacts with them and thus prevents Wnt binding to Fz receptors. We also describe the complex network of interactions among GPC3-modulated signaling pathways.

Conclusion

GPC3 is operating through an intricate molecular signaling network. From the balance of these interactions, the inhibition of breast metastatic spread induced by GPC3 emerges.

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Title: Signaling network involved in the GPC3-induced inhibition of breast cancer progression: role of canonical Wnt pathway
Authors: Dolores Fernández
Macarena Guereño
María Amparo Lago Huvelle
Magalí Cercato
María Giselle Peters
Publication date: 01-12-2018
Publisher: Springer Berlin Heidelberg
Published in: Journal of Cancer Research and Clinical Oncology / Issue 12/2018
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-018-2751-0

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