In the breast, cells are faced with the existential question common to many cells: differentiate or proliferate? In the 10 November Journal of Cell Biology, Michele Wozniak et al. consider this question in an in vitro system of epithelial breast differentiation. They examine how the flexibility of the extracellular matrix influences this critical decision.

Credit: Reprinted with permission from JCB

It has been known for years that breast epithelial cells differentiate into tubules (at right) if the cells are cultured in a three-dimensional collagen matrix floating in medium. But if the matrix is made more rigid by attachment to a surface, or more dense by increasing the collagen concentration, proliferation is favored. How do breast cells sense the flexibility of their surroundings? The investigators found that cells use contractile forces, generated through the small GTPase Rho, to sense structural stretch in the extracellular matrix. In a flexible matrix, cell contraction downregulates the small GTPase Rho and the focal adhesion kinase (FAK). In a rigid matrix, Rho is upregulated and FAK is enlisted to help clamp down the cells at matrix adhesion sites (inset; FAK in red, nuclei in blue). In addition to regulating cell stickiness, FAK also links to pathways that regulate proliferation and migration.

In the breast, epithelial cells must contend with numerous inputs. But in some women, cells face particularly dense breast tissue and high deposition of collagen. These women have a four- to six-fold increased risk of developing breast cancer.