Regulated expression and growth inhibitory effects of transforming growth factor-β isoforms in mouse mammary gland development

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Abstract
Transforming Growth Factor-βl (TGF-β1) was pre-viously shown to inhibit reversibly the growth of mouse mammary ducts when administered in vivo by miniature slow-release plastic implants. We now report a compara-tive analysis of three TGF-β isoforms with respect to gene expression and localization of protein products within the mouse mammary gland. Our studies revealed overlapping expression patterns of TGF-β 1, TGF-β 2 and TGF-β 3 within the epithelium of the actively-growing mammary end buds during branching morpho-genesis, as well as within the epithelium of growth-quiescent ducts. However, TGF-J83 was the only isoform detected in myoepithelial progenitor cells (cap cells) of the growing end buds and myoepithelial cells of the mature ducts. During pregnancy, TGF-β2 and TGF-β 3 transcripts increased to high levels, in contrast to TGF-β1 transcripts which were moderately abundant; TGF-β2 was significantly transcribed only during pregnancy. Molecular hybridization in situ revealed overlapping patterns of expression for the three TGF-β isoforms during alveolar morphogenesis, but showed that, in contrast to the patterns of TGF-β1 and TGF-β2 expression, TGF-β3 is expressed more heavily in ducts than in alveoli during pregnancy. Developing alveolar tissue and its associated ducts displayed striking TGF-β3 immunoreactivity which was greatly reduced during lactation. All three isoforms showed dramatically reduced expression in lactating tissue. The biological effects of active, exogenous TGF-β 2 and TGF-β3 were tested with slow-release plastic implants. These isoforms, like TGF-β1, inhibited mam-mary ductal elongation in situ by causing the disappear-ance of the proliferating stem cell layer (cap cells) and rapid involution of ductal end buds. None of the isoforms were active in inhibiting alveolar morphogenesis. We conclude that under the limited conditions of these tests, the three mammalian isoforms are functionally equival-ent. However, striking differences in patterns of gene expression and in the distribution of immunoreactive peptides suggest that TGF-β isoforms may have distinct roles in mammary growth regulation, morphogenesis and functional differentiation.