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.