Transforming growth factor-beta (TGF-beta) can stimulate or inhibit growth of cells in vitro, as well as induce the transformed phenotype. Although widely distributed in animal tissue, the effects of TGF-beta in vivo are largely unknown, and a physiological role for the peptide hormone has not been demonstrated. The effect of TGF-beta on developing epithelial tissue in situ was studied by using slow-release plastic pellets containing TGF-beta to treat developing mouse mammary gland. Powerful inhibition of mammary growth and morphogenesis was observed. This growth-inhibited mammary tissue was histologically normal, and the inhibitory effect was fully reversible. Under the conditions of these experiments, TGF-beta displayed many of the characteristics expected of a physiologically active growth-regulatory molecule.
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.
The product of the WT1 Wilms tumor suppressor gene controls the expression of genes encoding components of the insulin-like growth factor and transforming growth factor  signaling systems. The role of these growth factors in breast tumor growth led us to investigate possible WT1 gene expression in normal and cancerous breast tissue. WT1 was detected by immunohistochemistry in the normal mammary duct and lobule, and the patterns of expression were consistent with developmental regulation. In a survey of 21 infiltrating tumors, 40% lacked immunodetectable WT1 altogether and an additional 28% were primarily WT1-negative. Cytoplasmic, but not nuclear, localization of WT1 was noted in some tumor cells and WT1 was detected, sometimes at high levels, in more-advanced estrogenreceptor-negative tumors. In this highly malignant subset, the tumor suppressor protein p53, which can physically interact with WT1, was also sometimes detected. WT1 mRNA was detected in normal and tumor tissue by reverse transcription-coupled PCR. Alternative splicing of the WT1 mRNA may regulate gene targeting of the WT1 protein through changes either in its regulatory or zinc-finger domains. The relative proportions of WT1 mRNA splice variants were altered in a random sample of breast tumors, providing evidence that different tumors may share a common WT1-related defect resulting in altered regulation of target genes.
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