Triple-negative Breast Cancer (TNBC) is associated with an aggressive clinical history, development of recurrence, distant metastasis and shorter patient survival. Intriguingly, TNBC has activated the epithelial-mesenchymal transition (EMT) program, which is a cellular de-differentiation process that provides cells with the increased plasticity and stem cell-like properties required during embryonic development, tissue remodeling, wound healing and metastasis. Using unbiased protein purification coupled with mass spectrometry analysis, we identified that Snail and Twist, two key EMT-inducing transcriptional factors, act as transcriptional repressor and activator, respectively. Snail is a labile protein and is subjected to protein ubiquitination and degradation, and we have identified the protein kinase, phosphatase, ubiquitin E3 ligase and de-ubiquitinase in the regulation of Snail. Interestingly, the protein stability of Snail and its interaction with these effectors are controlled by signals from the tumor microenvironment, resulting in the EMT induction and invasive phenotypes that commonly observed at the tumor-stromal boundary. Our study provides new insights and opportunities for the development of effective therapeutic approaches against metastatic breast cancer.