Upregulation of invasion promoting molecules and subsequent activation of their downstream signaling targets are critical for the progression of cancer. Here, we demonstrate that AREG and EREG, which are established contributors of tumor progression14, 15, are upregulated downstream of signaling from integrin α6β4 and this upregulation is dependent on active DNA demethylation. This observation builds on our previous data showing that integrin α6β4 stimulates specific DNA demethylation of the S100A4 promoter, ultimately contributing to invasive capabilities of breast cancer cells11. Interestingly, work in squamous cell carcinoma and MDA-MB-231 breast cancer cells demonstrates that ECM content, cell-cell interactions, and 3D environment impact the methylation state of the E-cadherin promoter and this dynamic epigenetic plasticity helps drive EMT47, 48. These observations collectively solidify the role of the tumor microenvironment in regulating specific sites of DNA methylation, thus contributing to invasive growth of cancer cells.