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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

  • Preclinical Study
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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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Abbreviations

ALK5:

Activin receptor-like kinase 5

EPHB2:

Ephrin-type B receptor 2

EMT:

Epithelial–mesenchymal transition

MMP:

Matrix metallo proteinase

MTSS1:

Metastasis suppressor 1

PAI-1:

Plasminogen activator inhibitor-1

R-Smad:

Receptor-regulated Smad

TGF-β:

Transforming growth factor-β

TβRI/II:

TGF-β type I/II receptor

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Acknowledgments

We thank Dr. F. Miller for providing the MCF-10A1 and MCF-10CA1a cell lines, Dr. K. Iwata for providing TGF-β3, Dr. M. Kandouz for providing EPHB2 expression construct, and Dr. A. Levine and Dr. M. Maurice for providing anti-Mdm2 and anti-USP7 antibodies, respectively. We thank Dr. D. Baker for critically reading and editing the manuscript. This study was supported by Grants from Worldwide Cancer Research (formerly known as Association for International Cancer Research (09-0073) and Tumor Host Genomics (518198).

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The authors declare no conflict of interests.

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  1. Eliza Wiercinska

    Present address: German Red Cross Blood Donor Service Baden-Wuerttemberg-Hessen, Institute for Transfusion Medicine and Immunohematology, Johann Wolfgang Goethe University Hospital, Frankfurt, Germany

Authors and Affiliations

  1. Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands, Leiden University Medical Center, P.O. Box 9600, 2300 RC, Leiden, The Netherlands

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

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  1. Suzanne Lam
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Correspondence to Aart G. Jochemsen.

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Suzanne Lam and Eliza Wiercinska have equally contributed to this manuscript.

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10549_2014_3147_MOESM1_ESM.pdf

Supplementary material 1 (PDF 361 kb). Supplementary Fig. 1. PAI-1 expression is not inhibited by p53 activation. a MCF-10CA1a, b SK-BR-7, c SUM102PT cells were treated with 5 ng/ml TGF-β3 and/or 10 μM Nutlin-3 for 24 h. Total RNA was extracted, reverse transcribed and analyzed for PAI-1 mRNA expression by real-time PCR. Results are expressed as mean ± SD of triplicate wells. ***P < 0.001 compared to mock-treated cells

10549_2014_3147_MOESM2_ESM.pdf

Supplementary material 2 (PDF 313 kb). Supplementary Fig. 2. EPHB2 expression is induced by TGF-β3 in MCF-10A1 and MCF-10CA1a cells. MCF-10A1 and MCF-10CA1a cells were treated with 5 ng/ml TGF-β3 for 6 h. Total RNA was extracted, reverse transcribed and analyzed for PAI-1 mRNA expression by real-time PCR. Results are expressed as mean ± SD of triplicate wells

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Lam, S., Wiercinska, E., Teunisse, A.F.A.S. et al. 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. Breast Cancer Res Treat 148, 7–18 (2014). https://doi.org/10.1007/s10549-014-3147-8

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