EGFR‐induced EMT is modulated by the ECM: the role of hyaluronan in the inhibition of breast cancer metastasis

Abstract

Metastasis requires cells to undergo epithelial-to-mesenchymal transition (EMT). The epidermal growth factor receptor (EGFR) can induce metastasis and promote EMT. The extracellular glycoprotein, hyaluronan (HA), can modulate EGFR activity. In human breast carcinoma, HA is produced in a matrix-embedded form and found in the ECM surrounding tumor cells, but experimentally it is often used in soluble form. We examined EGFR activation in cells grown on either collagen-embedded HA or soluble HA. We found that embedded HA downregulates EGFR while soluble HA upregulates EGFR. Therefore, we hypothesized that collagen-embedded HA inhibits EGFR-driven EMT. To address this we examined expression of EMT markers TWIST, E-cadherin, and vimentin in response to embedded or soluble HA. We found that in the presence of soluble HA EGF induces TWIST expression while suppressing E-cadherin. Conversely, EGF-treated cells grown on embedded HA express E-cadherin and fail to express TWIST. Additionally, collagen-embedded HA inhibits vimentin expression and invadopodia formation. Finally, we examined the ability of EGF to induce morphological changes characteristic of EMT and found that embedded HA delays these changes. These data highlight the importance of recapitulating the epithelial-stromal interactions that occur in vivo and demonstrate how the ECM plays a significant role in EMT, a process critical to metastasis.