INHIBITION OF MAMMARY DUCT DEVELOPMENT BUT NOT ALVEOLAR OUTGROWTH DURING PREGNANCY IN TRANSGENIC MICE EXPRESSING ACTIVE TGF-BETA-1

The transforming growth factors beta (TGFs-beta) are potent inhibitors of cell proliferation and are usually secreted in a latent form. TGF- beta1, TGF-beta2, and TGF-beta3 are expressed in distinct but overlapp ing patterns in the developing mouse mammary gland. To study the role of transforming growth factor-beta1 (TGF-beta1) in normal mammary deve lopment and in mammary neoplasia, we have constructed three transgenic mouse lines that express a simian TGF-beta1S223/225 mutated to produc e a constitutively active product under the control of the MMTV enhanc er/promoter. Expression of the transgene, as confirmed by in situ hybr idization, immunohistochemistry, and Northern blot analysis, was assoc iated with marked suppression of the normal pattern of mammary ductal tree development in female transgenics. Reduction in total ductal tree volume was observed at 7 weeks, soon after estrous begins, and was mo st apparent at 13 weeks, as ductal growth in the normal mammary gland declines. This effect was seen in all three lines. However, during pre gnancy, alveolar outgrowths developed from the hypoplastic ductal tree , and lactation occurred, therefore, all transgenic females could feed full litters. Unlike many other transgenic mouse models in which expr ession of growth factors or oncogenes under control of the MMTV promot er leads to mammary epithelial hyperplasia and increased tumor formati on, the MMTV-TGF-beta1S223/225 transgene causes conditional hypoplasia of the mammary ductal tree and no spontaneous tumors have been detect ed in the MMTV-TGF-beta1S223/225 transgenic animals.