TGF-β-Smad2 dependent activation of CDC 25A plays an important role in cell proliferation through NFAT activation in metastatic breast cancer cells

Abstract

In late stages of cancer, TGF-β promotes the metastasis process by enhancing the invasiveness of cancer cells and inducing the epithelial-to-mesenchymal transition (EMT), a process that is concomitantly associated with breast cancer metastasis. Metastasis comprises of multiple steps with the regulation of complex network of signaling. Metastasis is associated with both the EMT and cell proliferation, but yet it has not been clearly distinguished how the balance between the cell proliferation and EMT is maintained together. Recently, it has been accounted that a transcription factor, NFAT has an important role for switching tumor suppressive to progressive effect of TGF-β and NFAT has a role in TGF-β mediated EMT by regulating N-cadherin. CDC 25A phosphatase, an important cell cycle regulator is overexpressed in breast cancer. Our results demonstrate that TGF-β regulating the CDC 25A in a Smad2 dependent way, translocates NFAT to nucleus and NFAT in co-operation with Smad2 promotes the tumor progression by upregulating the CDK2, CDK4, and cyclin E. This result signifies that TGF-β by regulating NFAT in different ways maintains the balance between EMT and cell proliferation mechanism concurrently during the late stage of breast cancer.