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Regulation of mammary growth and function by TGF-beta
1Department of Biology, University of California, Thimann Laboratories, Santa Cruz 95064.
Abstract:
We have previously shown that TGF-beta 1 rapidly and reversibly inhibits ductal growth in vivo when administered by miniature slow-release plastic implants. A possible role for endogenous TGF-beta 1 was suggested by the observation that the normal gland displayed substantial, developmentally regulated levels of TGF-beta 1 transcripts and protein. These studies have now been extended to include the other two mammalian TGF-beta isoforms. When tested with slow-release plastic implants, TGF-beta 2 and TGF-beta 3 also caused disappearance of the proliferating mammary stem cell layer, with rapid involution of ductal end buds and cessation of glandular growth. None of the isoforms was active in inhibiting alveolar morphogenesis. We conclude that under the conditions of these tests, the three mammalian isoforms are functionally equivalent. However, striking differences in patterns of gene expression and in the distribution of immunoreactive peptides suggest that TGF-beta 2 was expressed only at low levels, and mainly during pregnancy. TGF-beta 3 was expressed in ductal stroma and epithelium, and was the only isoform detected in myoepithelial cells. Developing alveolar tissue and its associated ducts displayed striking TGF-beta 3 gene expression and immunostaining, which were greatly reduced during lactation. We are now investigating the possibility that the observed high levels of TGF-beta expression in pregnancy, particularly of TGF-beta 3, and the absence of substantial expression of any isoform during lactation, may indicate a role for the TGF-beta in regulating functional differentiation or the onset of milk secretion.
Insights
Transforming growth factor-beta (TGF-β) isoforms 2 and 3 inhibit mammary ductal growth, similar to TGF-β 1. Their expression patterns suggest roles in pregnancy and lactation regulation.
Area of Science:
- Developmental Biology
- Cell Biology
- Endocrinology
Background:
- Previous studies demonstrated that TGF-β 1 inhibits mammary ductal growth in vivo.
- Endogenous TGF-β 1 levels are developmentally regulated in normal mammary glands.
Purpose of the Study:
- To investigate the effects of TGF-β 2 and TGF-β 3 on mammary gland development.
- To compare the functional equivalence and expression patterns of TGF-β isoforms in mammary gland development.
Main Methods:
- Administration of TGF-β 2 and TGF-β 3 via slow-release implants in vivo.
- Analysis of gene expression and protein distribution of TGF-β isoforms.
- Assessment of effects on ductal and alveolar morphogenesis.
Main Results:
- TGF-β 2 and TGF-β 3, like TGF-β 1, inhibited ductal growth and involution of end buds.
- No isoform affected alveolar morphogenesis.
- Distinct expression patterns were observed: TGF-β 2 mainly during pregnancy, TGF-β 3 in ductal tissues and myoepithelial cells, with reduced expression during lactation.
Conclusions:
- The three mammalian TGF-β isoforms are functionally equivalent in inhibiting ductal growth under tested conditions.
- Differential expression patterns suggest specific roles for TGF-β 2 and TGF-β 3 in regulating mammary gland differentiation and function during pregnancy and lactation.