Misregulated proteolysis has been linked to the initiation and progression of a large number of pathological processes. Transcriptional analysis of primary tumors and cell lines in breast cancer identified differential expression of proteases and protease inhibitors associated with different molecular subtypes. However, due to the tight regulation of protease activity post-translationally, it is not sufficient to know protease expression levels alone. Here, we used an unbiased global protease profiling approach to analyze changes in extracellular proteolysis in an isogenic cell line model, MCF10A HER2, representative of the HER2 subtype, with the goal of identifying proteases contributing to the oncogenic potential of HER2 in breast cancer. HER2 expression revealed changes consistent with activation of TGF-beta signaling. Specifically, we determined that a metalloprotease involved in TGF-beta activation, BMP1, was upregulated at both the protein and activity level. In summary, through global identification of extracellular proteolysis, we elucidate proteolysis associated with HER2-mediated signaling.