In cell culture, type a transforming growth factor (TGF-a) stimulates epithelial cell growth, whereas TGF-p1 overrides this stimulatory effect and is growth inhibitory. Transgenic mice that overexpress TGF- In contrast to the TGF-ps, TGF-a is a mitogen for most cell types (7) and may also play a significant role in mammary gland development. TGF-a is localized in vivo in the epithelium of the advancing terminal buds and in stromal fibroblasts at the base of terminal buds (8). Furthermore, implantation of pellets containing TGF-a into regressed mammary glands of ovariectomized mice stimulates the reappearance of end buds (8). MMTV-TGF-a transgenic mice exhibit enhanced production of TGF-a in the smaller ducts of the mammary gland (9). These mice exhibit mammary epithelial hyperplasia with a marked increase in the rate of benign and malignant mammary tumor development (9,10 MATERIALS AND METHODSTransgene Detection. Transgenic mice were identified by Southern blot analysis with a probe made from either mouse TGF-31 or an EcoRI/Xho I fragment of the transgene construct containing 526 bp of rabbit P-globin exon 3 sequence as described (6). The MMTV-TGF-a transgene was detected by PCR as described (9).Transgenic Mice. The MMTV-TGF-a and MMTV-TGF-31 transgenic animals were generated in a (C57BL x DBA/2)F1 (B6D2F1) background, which has a low frequency of spontaneous mammary tumor formation (6,(9)(10)(11). Wild-type animals used in various experiments were from the same genetic background. For the crossbreeding experiments, the line 29 MMTV-TGF-a transgenic mouse line was selected (9,10

The transforming growth factors 13 (TGFs-[3) are potent inhibitors of cell proliferation and are usually secreted in a latent form. TGF-IM, TGF-B2, and TGF-I33 are expressed in distinct but overlapping patterns in the developing mouse mammary gland. To study the role of transforming growth factor-B1 (TGF-I31) in normal mammary development and in mammary neoplasia, we have constructed three transgenic mouse lines that express a simian TGF-B1 s223/22s mutated to produce a constitutively active product under the control of the MMTV enhancer/promoter. Expression of the transgene, as confirmed by in situ hybridization, immunohistochemistry, and Northern blot analysis, was associated 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 most apparent at 13 weeks, as ductal growth in the normal mammary gland declines. This effect was seen in all three lines. However, during pregnancy, 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 expression of growth factors or oncogenes under control of the MMTV promoter leads to mammary epithelial hyperplasia and increased tumor formation, the MMTV-TGF-~I s223/22s transgene causes conditional hypoplasia of the mammary ductal tree and no spontaneous tumors have been detected in the MMTV-TGF-[~I s223/22s transgenic animals.