| The mammary gland consists of a polarized epithelium surrounded by a basement membrane matrix, forming a series of branching ducts ending in hollow, sphere-like acini. Essential roles for the epithelial basement membrane during acinar differentiation, in particular laminin and its integrin receptors, have been identified using mammary epithelial cells cultured on a reconstituted basement membrane. However, contributions from fibronectin, which is abundant in the mammary gland during development and tumorigenesis, have not been fully examined. Here we show that altering fibronectin levels disrupts acinar organization by modulating mitogenesis. During development depletion of endogenous fibronectin or addition of exogenous fibronectin resulted in under or over-proliferation of mammary epithelial cells, respectively, both changes impeding proper acinar differentiation. Further, addition of fibronectin was sufficient to promote over-proliferation and reverse established growth-arrest of mammary epithelial cells within differentiated acini. These proliferative changes negatively impacted formation and maintenance of proper acinar morphology. Fibronectin expression by mammary epithelial cells was dynamically regulated during the morphogenic process. While signals from the basement membrane matrix repressed fibronectin production, fibronectin production by mammary epithelial cells was up-regulated by exposure to extracellular fibronectin suggesting a positive-feedback mechanism. These results show that fibronectin provides signals permissive for cell growth, contrary to the differentiation signals from the basement membrane. These effects suggest a link between increased fibronectin and proliferation of mammary epithelial cells during development and oncogenesis in the mammary gland. |
