Le et al. identify a signaling circuit that may protect breast epithelial cells from the tumorigenic effects of stiff extracellular matrices.
Changes in the extracellular matrix can stiffen tissues and activate oncogenic signaling pathways, but cells may try to protect themselves by remodeling their cytoskeleton and cell–matrix adhesions. ROBO receptors and their extracellular SLIT ligands—best known for their role in axonal guidance—regulate Rho family GTPases and the actin cytoskeleton, and may therefore help cells sense and respond to such changes in their environment.
Le et al. examined the ROBO signaling pathway in breast epithelial cells and found that ROBO1 and its ligand SLIT2 enhance cellular contractility by activating the Rac GTPase and stimulating assembly of cell–matrix adhesions. Stiffer environments caused breast cells to down-regulate a microRNA, miR-203, that normally suppresses Robo1, thereby elevating ROBO1 protein levels. This, in turn, enhanced cellular contractility and adhesion, allowing cells to retain their shape and position within stiff extracellular matrices.
Breast cancer cells lacking Robo1 were more invasive, suggesting that the up-regulation of ROBO1 in stiff environments may prevent cells from metastasizing. Moreover, ROBO1 has previously been shown to suppress cell proliferation, suggesting that this pathway could delay tumor progression. Accordingly, breast cancer patients whose tumors displayed low miR-203/high Robo1 expression had better long-term survival rates. Senior author Lindsay Hinck now wants to confirm that ROBO1 can counteract the protumorigenic effects of tissue stiffening in both mice and humans.