Inhibition of ductal morphogenesis in the mammary gland of WAP-Fgf4 transgenic mice

We previously demonstrated that expression of human FGF4 in the epithelial compartment of murine mammary glands caused hyperplasia during lactation and a dramatic delay in gland involution due to inhibition of cellular apoptosis. We now analyse the effects of transgene expression during development of the organ. Expression of WAP-Fgf4 initiate with the onset of sexual hormones (4 weeks of age), and defects in morphogenesis of the organ were already apparent at 5 weeks of age and persisted throughout all stages of post-natal development. These defects involved ductal development, but not lobuloalveolar morphogenesis, and were due to a decrease in the level of apoptosis within the terminal end buds. We also show that regulation of apoptosis by FGF4 in the mammary gland, both during development and involution, could occur via inhibition of Bcl2 expression. Overall our data demonstrate that FGF4 is a regulator of mammary epithelial cells apoptosis during all stages in which programmed cell death is an important mechanism of development, namely morphogenesis and involution. We also suggest that this growth factor could act by interfering with the Bcl2 pathway.