Wild-type p53 inhibits pro-invasive properties of TGF-ß3 in breast cancer, in part through regulation of EPHB2, a new TGF-ß target gene.
Breast Cancer Res Treat
; 148(1): 7-18, 2014 Nov.
Article
en En
| MEDLINE
| ID: mdl-25257729
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-ß (TGF-ß) 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-ß3 in these processes. MCF-10A1 and MCF-10CA1a breast cancer cells were treated with Nutlin-3 and TGF-ß3, 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-ß3 on EMT were examined in NMuMG cells. To identify genes involved in TGF-ß-induced invasion that are modulated by p53, a Human Tumor Metastasis-specific RT-PCR array was performed. Verification of EPHB2 regulation by TGF-ß3 and p53 was performed on breast cancer tumor cell lines. We demonstrate that p53 inhibits basal and TGF-ß3-induced invasion, migration, and EMT in normal breast epithelial and breast cancer cells. Pharmacological activation of p53 inhibited induction of several TGF-ß3 targets involved in TGF-ß3-induced tumor cell invasion, i.e., matrix metallo proteinase (MMP)2, MMP9, and integrin ß 3 . The ephrin-type B receptor 2 (EPHB2) gene was identified as a new TGF-ß target important for TGF-ß3-mediated invasion and migration, whose transcriptional activation by TGF-ß3 is also inhibited by p53. The results show an intricate interplay between p53 and TGF-ß3 whereby p53 inhibits the TGF-ß3-induced expression of genes, e.g., EPHB2, to impede tumor cell invasion and migration.
Texto completo:
1
Colección:
01-internacional
Asunto principal:
Neoplasias de la Mama
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Proteína p53 Supresora de Tumor
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Receptor EphB2
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Factor de Crecimiento Transformador beta3
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Invasividad Neoplásica
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Breast Cancer Res Treat
Año:
2014
Tipo del documento:
Article