Fibronectin fragments induce MMP activity in mouse mammary epithelial cells: evidence for a role in mammary tissue remodeling

Mammary gland form and function are regulated by interactions between epith elium and extracellular matrix. Major glycoprotein components of extracellu lar matrix have been identified that give survival, proliferation and diffe rentiation signals to mammary epithelial cells, We provide evidence that pr oteolytic fragments of the extracellular matrix glycoprotein, fibronectin, suppress growth and can promote apoptosis of mouse mammary epithelial cells . During mammary gland involution, total fibronectin and fibronectin fragme nt levels are increased. The peak levels of fibronectin protein and fragmen ts are observed 4-6 days post-weaning, coincident with the peak in epitheli al cell death. Using a model for hormone withdrawal-induced death of mammar y epithelium, elevated levels of fibronectin proteolytic fragments were ass ociated with apoptosis in TM-6 cells, a tumorigenic mouse mammary epithelia l cell line, Treatment of TM-6 cells,vith exogenous fibronectin fragments ( FN120) reduced cell number, and induced apoptosis and matrix degrading prot ease activity. Inhibition of matrix protease activity rescued TM-6 cell via bility, indicating that FN120-induced cell loss is mediated through matrix protease activity. In a three-dimensional model for mammary gland developme nt, FN120 reduced alveolar-like and promoted ductal-like development by a m atrix protease-dependent mechanism. These data suggest that during post-lac tational involution, fibronectin fragments may contribute to epithelial cel l loss and dissolution of mammary alveoli by inducing matrix degrading prot einases.