Transforming growth factor-β 1 enhances the invasiveness of breast cancer cells by inducing a Smad2-dependent epithelial-to-mesenchymal transition

Abstract

Metastasis is unequivocally the most lethal aspect of breast cancer and the most prominent feature associated with disease recurrence, the molecular mechanisms whereby epithelial-to-mesenchymal transition (EMT) mediates the initiation and resolution of breast cancer metastasis remains poorly understood. Transforming growth factor-β1 (TGF-β1) is a multifunctional cytokine that is intimately involved in regulating numerous physiological processes, including cellular differentiation, homeostasis and EMT. Recent findings have implicated high levels of TGF-β1 were associated with poor outcome, whereas inhibition of TGF-β signaling reduces metastasis in breast cancer, suggesting that the chemo-therapeutic targeting of TGF-β1 or TGF-β signaling may offer new inroads in ameliorating metastatic disease in breast cancer patients. In this study, we showed immunohistochemical evidence for EMT, which is associated with TGF-β1 expression, at the invasion front of breast cancer in vivo. The data also indicated that human breast cancer cell lines, MCF-7 and MDA-MB-435S, of epithelial cell characteristics were induced to undergo EMT by TGF-β1 and dependent on the Smad2 signaling pathway. Following TGF-β1 treatment, cells showed dramatic morphological changes assessed by phase contrast microscopy, accompanied by decreased epithelial marker and increased mesenchymal markers. Importantly, cell invasion was also enhanced in the EMT process, while knockdown of the Smad2 gene by silencing siRNA partially inhibited these effects in MDA-MB435S (P<0.05). These data suggested that EMT of breast cancer induced by TGF-β1 is dependent on Smad2 signaling and promotes breast cancer cell metastasis.

RETRACTED: Silencing of Prrx1b suppresses cellular proliferation, migration, invasion and epithelial–mesenchymal transition in triple‐negative breast cancer

“…Among them, mesenchymal transition of cancer cells, termed as epithelial-mesenchymal transition (EMT), has drawn much attention in breast cancer metastasis research [6,7]. During EMT, epithelial cells lose polarity and E-cadherin mediated adhesion at the adherens junctions.…”

Estradiol, TGF-β1 and hypoxia promote breast cancer stemness and EMT-mediated breast cancer migration

“…In addition, TGF-β1 acts as a tumor suppressor in the early stages of breast carcinoma, and is involved in the progression of tumors by resisting inhibited cell growth during the later stages of disease (25). TGF-β1 also enhances breast cancer metastasis by inducing Smad family member 2 (Smad2) (26). However, the regulatory mechanisms of breast CSCs following treatment with E2 or TGF-β1 have not been investigated.…”

Silencing of Prrx2 Inhibits the Invasion and Metastasis of Breast Cancer both In Vitro and In Vivo by Reversing Epithelial-Mesenchymal Transition

“…Epithelial-mesenchymal transition (EMT) has been demonstrated to promote cell invasion, leading to tumor cell metastasis in various cancers, including breast cancer [5, 6]. During the EMT, epithelial cells lose apical-basal polarity and their junctions, acquire the motility and the invasiveness properties of mesenchymal cells characterized by the down-regulation of cell-cell adhesion molecules, such as E-cadherin, claudins and occludin and the up-regulation of vimentin, fibronectin and N-cadherin [7, 8]. Conversely, the mesenchymal-epithelial transition (MET) describes the reverse process.…”