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Breast Cancer Research and Treatment
Published in: Breast Cancer Research and Treatment 1/2014

01-11-2014 | Preclinical Study

Wild-type p53 inhibits pro-invasive properties of TGF-β3 in breast cancer, in part through regulation of EPHB2, a new TGF-β target gene

Authors: Suzanne Lam, Eliza Wiercinska, Amina F. A. S. Teunisse, Kirsten Lodder, Peter ten Dijke, Aart G. Jochemsen

Published in: Breast Cancer Research and Treatment | Issue 1/2014

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Abstract

The p53 tumor suppressor protein is primarily known for its important role in tumor suppression. In addition, p53 affects tumor cell migration, invasion, and epithelial-mesenchymal transition (EMT); processes also regulated by the transforming growth factor-β (TGF-β) signaling pathway. Here, we investigated the role of p53 in breast tumor cell invasion, migration, and EMT and examined the interplay of p53 with TGF-β3 in these processes. MCF-10A1 and MCF-10CA1a breast cancer cells were treated with Nutlin-3 and TGF-β3, and the effects on tumor cell migration and invasion were studied in transwell and 3D spheroid invasion assays. The effects of Nutlin-3 and TGF-β3 on EMT were examined in NMuMG cells. To identify genes involved in TGF-β-induced invasion that are modulated by p53, a Human Tumor Metastasis-specific RT-PCR array was performed. Verification of EPHB2 regulation by TGF-β3 and p53 was performed on breast cancer tumor cell lines. We demonstrate that p53 inhibits basal and TGF-β3-induced invasion, migration, and EMT in normal breast epithelial and breast cancer cells. Pharmacological activation of p53 inhibited induction of several TGF-β3 targets involved in TGF-β3-induced tumor cell invasion, i.e., matrix metallo proteinase (MMP)2, MMP9, and integrin β 3 . The ephrin-type B receptor 2 (EPHB2) gene was identified as a new TGF-β target important for TGF-β3-mediated invasion and migration, whose transcriptional activation by TGF-β3 is also inhibited by p53. The results show an intricate interplay between p53 and TGF-β3 whereby p53 inhibits the TGF-β3-induced expression of genes, e.g., EPHB2, to impede tumor cell invasion and migration.
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Metadata
Title
Wild-type p53 inhibits pro-invasive properties of TGF-β3 in breast cancer, in part through regulation of EPHB2, a new TGF-β target gene
Authors
Suzanne Lam
Eliza Wiercinska
Amina F. A. S. Teunisse
Kirsten Lodder
Peter ten Dijke
Aart G. Jochemsen
Publication date
01-11-2014
Publisher
Springer US
Published in
Breast Cancer Research and Treatment / Issue 1/2014
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-014-3147-8

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