page 583. This matrix-sensing pathway may explain why carcinoma risk is increased in women with fibrous breast tissue.
Differentiation of breast epithelial cells into tubules occurs in vitro if the cells are cultured in a 3D collagen matrix floating in medium. If the same matrix is made more rigid by attachment to a surface, tubulogenesis is disrupted, indicating that breast cells sense the flexibility of their surroundings. Wozniak et al. now find that the small GTPase Rho and its effector, ROCK, are essential for the cells to pull against the matrix and to respond to the resistance encountered.
The breast epithelial cells attach to their collagenous matrix via integrin receptors, which regulate Rho/ROCK-mediated actin–myosin contractility. The authors show that if the cells are able to contract their matrix, as in the floating 3D gels, Rho is down-regulated and the focal adhesion protein FAK is scattered throughout the cell. As expected, these cells differentiate into tubules—a process that may require matrix flexibility to work efficiently. In contrast, if the matrix is made too rigid for cells to contract (e.g., by increasing collagen levels in the floating gels), Rho activity remains high and FAK is found at matrix adhesion sites—a sign of strengthened contact points.
When FAK is at adhesions, the cells proliferate rather than form tubules, indicating that strengthened matrix contacts send a mitotic signal, although its exact identity is unknown. A pathological increase in matrix deposition, as found in dense breast tissue and in fibroids, and the resulting increased rigidity are thus expected to cause abnormal proliferation that might promote breast cancer. The authors are currently using a mouse model with dense collagen breast tissue to test this theory. ▪