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TGF-β and functional differentiation

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Abstract

A review of the pertinent literature suggests that TGF-β1 may play a multifaceted role in functional differentiation of mammary epithelium. Evidence for the expression of TGF-β1 RNA and the presence of functional TGF-β1 protein in differentiating mammary epithelial cells from a pregnant mouse has been recently reported. The specific role of mammary-epithelial-cell-produced TGF-β1 in the differentiating mammary gland is presently unclear. However, several possible functions are suggested from the following observations. Milk protein production is negatively regulated by exogenous TGF-β1 during gestational development of the gland but not during lactation. Consistent with reports linking TGF-β1 gene expression with mammary gland involution following lactation, overexpression of TGF-β1 in the differentiating secretory epithelium leads to premature programmed cell death in the absence of a negative effect on secretory epithelial cell proliferation. A role for TGF-β1 in cell cycle control and suppression of malignant progression independent from its inhibitory effect on epithelial cell growth has been demonstrated in keratinocytes. A similar function could provide protection against malignancy in proliferating mammary epithelium and account for TGF-β1 suppression of mammary tumorigenesis in transgenic mice overexpressing transforming growth factor alpha (TGF-α).3

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Abbreviations

MMTV-LTR:

Mouse mammary tumor virus Long Terminal Repeat gene promoter

WAP:

whey acidic protein

TGF-β:

transforming growth factor beta

TGF-α:

transforming growth factor alpha

Met:

metallothionein gene promoter

LacZ:

E. coli beta-galactosidase

References

  1. A. B. Kulkarni, C-G. Huh, D. Becker, A. Geiser, M. Lyght, K. C. Flanders, A. B. Roberts, M. B. Sporn, J. M. Ward, and S. Karlsson (1993). Transforming growth factor β1 null mutation in mice causes excessive inflammatory response and early death.Proc. Natl. Acad. Sci. U.S.A. 90:770–774.

    PubMed  CAS  Google Scholar 

  2. A. Vassalli, M. M. Matzuk, H. A. R. Gardner, L. Kuo-Fen, and R. Jaenisch (1994). Activin/ Inhibin βB subunit gene disruption leads to defects in eyelid development and female reproduction.Genes Devel. 8:414–427.

    PubMed  CAS  Google Scholar 

  3. H. Schrewe, M. Gendron-Maguire, M. L. Harbison, and T. Gridley (1994). Mice homozygous for a null mutation of activin βB are viable and fertile.Mech. Dev. 47:43–51.

    PubMed  CAS  Google Scholar 

  4. I. H. Russo and J. Russo. (1994). Role of hCG and inhibin in breast cancer (Review).Int. J. Oncol. 4:297–306.

    CAS  Google Scholar 

  5. A. E. Gorska, R. Serra, R.-H. Chen, R. Derynck, and H. L. Moses (1995). Mammary gland development in transgenic mice expressing a dominant-negative transforming growth factor-beta type II receptor under the control of the mouse mammary tumor virus promoter/enhancer.Proc. Am. Assoc. Cancer Res. 36:188.

    Google Scholar 

  6. D. F. Pierce, M. D. Johnson, Y. Matsui, S. D. Robinson, L. I. Gold, A. F. Purchio, C. W. Daniel, B. L. M. Hogan, and H. L. Moses (1993). Inhibition of mammary duct development but not alveolar outgrowth during pregnancy in transgenic mice expressing active TGF-β1.Genes Devel. 7:2308–2317.

    PubMed  CAS  Google Scholar 

  7. S. Okamoto and T. Oka (1984). Evidence for physiological function of epidermal growth factor: Pregestational sialoadenectomy of mice decreases milk production and increases off-spring mortality during lactation period.Proc. Natl. Acad. Sci. U.S.A. 81:6059–60638.

    PubMed  CAS  Google Scholar 

  8. P. Hardman, E. Landels, A. S. Woolf, and B. S. Spooner (1994). TGF-β1 inhibits growth and branching morphogenesis in embryonic mouse submandibular and sublingual glandsin vitro.Devel. Growth Diff. 36:567–577.

    CAS  Google Scholar 

  9. C. Jhappan, A. G. Geiser, E. C. Kordon, D. Bagheri, L. Hennighausen, A. B. Roberts, G. H. Smith, and G. Merlino (1993). Targeting of a transforming growth factor β1 transgene to the pregnant mammary gland inhibits alveolar development and lactation.Embo J. 12:1835–1845.

    PubMed  CAS  Google Scholar 

  10. E. C. Kordon, R. A. McKnight, C. Jhappan, L. Hennighausen, G. Merlino, and G. H. Smith (1995). Ectopic TGF-β1 expression in the secretory mammary epithelium induces early senecence of the epithelial stem cell population.Devel. Biol. 168:47–61.

    CAS  Google Scholar 

  11. T. Yamamoto, H. Komura, K. Morishige, C. Tadokoro, M. Sakata, H. Kurachi, and A. Miyake (1994). Involvement of autocrine mechanism of transforming growth factor-β1 in the functional differentiation of pregnant mouse mammary gland.Eur. J. Endocrinol. 130:302–307.

    Article  PubMed  CAS  Google Scholar 

  12. M. Mieth, F. D. Boehmer, R. Ball, B. Groner, and R. Grosse (1990). Transforming growth factor-β inhibits lactogenic hormone induction of b-casein expression in HC-11 mouse mammary epithelial cells.Growth Factors 4:9–15.

    PubMed  CAS  Google Scholar 

  13. S. D. Robinson, A. B. Roberts, and C. W. Daniel (1993). TGF-β suppresses casein synthesis in mouse mammary explants and may play a role in controlling milk levels during pregnancy.J. Cell Biol. 120:245–251.

    PubMed  CAS  Google Scholar 

  14. A. W. Sudlow, C. J. Wilde, and R. D. Burgoyne (1994). Transforming growth factor-β1 inhibits casein secretion from differentiating mammary-gland explants but not from lactating mammary cells.Biochem. J. 304:333–336.

    PubMed  CAS  Google Scholar 

  15. C. S. Nicoll and H. A. Tucker (1965). Estimates of parenchymal, stromal, and lymph node deoxyribonucleic acid in mammary glands of C3H/Crgl/2 mice.Life Sci. 4:993–1001.

    PubMed  CAS  Google Scholar 

  16. D. F. Pierce, A. E. Gorska, A. Chytil, K. S. Meise, D. L. Page, R. J. Coffey, and H. L. Moses (1995). Mammary tumor suppression by transforming growth factor b1 transgene expression.Proc. Natl. Acad. Sci. U.S.A. 92:4254–4258.

    PubMed  CAS  Google Scholar 

  17. R. Strange, F. Li, S. Saurer, A. Burkhardt, and R. R. Friis (1992). Apoptotic cell death and tissue remodelling during mouse mammary gland involution.Development 115:49–58.

    PubMed  CAS  Google Scholar 

  18. A. Marti, B. Jehn, E. Costello, N. Keon, G. Ke, F. Martin, and R. Jaggi (1994). Protein kinase A and AP-1 (c-Fos/JunD) are induced during apoptosis of mouse mammary epithelial cells.Oncogene 9:1213–1223.

    PubMed  CAS  Google Scholar 

  19. S. A. Halter, P. Dempsey, M. Yasuhisa, K. Stokes, R. Graves-Deal, B. L. M. Hogan, and R. J. Coffey (1992). Distinctive patterns of hyperplasia in transgenic mice with mouse mammary tumor virus transforming growth factor-α.Am. J. Pathol. 140:1131–1146.

    PubMed  CAS  Google Scholar 

  20. G. H. Smith, R. Sharp, E. K. Kordon, C. Jhappan, and G. Merlino (1995). Transforming growth factor-α promotes mammary tumorigenesis through selective survival and growth of secretory epithelial cells.Am. J. Pathol. 147:1081–1095

    PubMed  CAS  Google Scholar 

  21. G. H. Smith (1996). Experimental mammary morphogenesis in anin vivo model: Evidence for distinct cellular progenitors of the ductal and lobular phenotype.Breast Cancer Res. Treat. 39:21–31.

    PubMed  CAS  Google Scholar 

  22. G. B. Silberstein, K. C. Flanders, A. B. Roberts, and C. W. Daniel (1992). Regulation of mammary morphogenesis: Evidence for extracellular matrix-mediated inhibition of ductal budding by transforming growth factor-β1.Devel. Biol. 152:354–362.

    CAS  Google Scholar 

  23. C. H. Streuli, C. Schmidhauser, M. Kobrin, M. J. Bissell, and R. Derynck (1993). Extracellular matrix regulates expression of the TGF-β1 gene.J. Cell Biol. 120:253–260.

    PubMed  CAS  Google Scholar 

  24. W. Cui, D. J. Fowlis, F. M. Cousins, E. Duffie, S. Bryson, A. Balmain, and R. J. Akhurst (1995). Concerted action of TGF-β1 and its type II receptor in transgenic mice.Genes Devel. 9:945–955.

    PubMed  CAS  Google Scholar 

  25. C. W. Daniel, Stephen Robinson, and Gary B. Silberstein (1996). The role of TGF-β in patterning and growth of the mammary ductal tree.J. Mam. Gland Biol. Neoplasia 1:331–341.

    CAS  Google Scholar 

  26. A. B. Glick, M. M. Lee, N. Darwiche, A. B. Kulkarni, S. Karlsson, and S. H. Yuspa (1994). Targeted deletion of the TGF-β1 gene causes rapid progression to squamous cell carcinoma.Genes Devel. 8:2429–2440.

    PubMed  CAS  Google Scholar 

  27. N. M. Shah, A. K. Groves, and D. J. Anderson (1996). Alternative neural crest cell fates are instructively promoted by TGF-β superfamily members.Cell 85:331–343.

    PubMed  CAS  Google Scholar 

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  1. Oncogenetics Section, Laboratory of Tumor Immunology and Biology, National Cancer Institute, 20892-1750, Bethesda, Maryland

    Gilbert H. Smith

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Smith, G.H. TGF-β and functional differentiation. J Mammary Gland Biol Neoplasia 1, 343–352 (1996). https://doi.org/10.1007/BF02017390

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