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Role of mesenchymal-epithelial interactions in mammary gland development

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Abstract

The mammary gland is a hormone-target organ derived from epidermis and develops as a result of reciprocal mesenchymal-epithelial interactions. The induction of mammary differentiation from indifferent epidermal cells by mammary mesenchyme implies induction of the complement of hormone receptors characteristic of normal mammary epithelium in cells of the epidermis. Considering the facts that mammary epithelial differentiation is induced by mammary mesenchyme and that certain aspects of hormone response (androgen-induced mammary regression) are inextricably linked to mesenchymal-epithelial interactions, it is evident that the biology of the mammary gland arises from and is maintained via cell-cell interactions. As a corollary, perturbation of stromal-epithelial interactions in adulthood may play a role in mammary carcinogenesis and in turn may provide opportunities for differentiation therapy.

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References

  1. C. C. Boring, T. S. Squires, and T. Tong (1992). Cancer statistics, 1992.Ca Cancer J. Clin. 4219–38.

    PubMed  Google Scholar 

  2. G. R. Cunha, A. A. Donjacour, P. S. Cooke, S. Mee, R. M. Bigsby, S. J. Higgins, and Y. Sugimura (1987). The endocrinology and developmental biology of the prostate.Endocrine Rev. 8338–363.

    Google Scholar 

  3. T. Sakakura (1991). New aspects of stroma-parenchyma relations in mammary gland differentiation.Int. Rev. Cytol. 125165–202.

    PubMed  Google Scholar 

  4. K. Haffen, M. Kedinger, and P. Simon-Assmann (1987). Mesenchyme-dependent differentiation of epithelial progenitor cells in the gut.J. Pediatr. Gastroenterol. Nutr. 614–23.

    PubMed  Google Scholar 

  5. T. Sakakura (1987). Mammary embryogensis. In C. W. Neville and M. C. Daniel (eds.),The Mammary Gland: Development, Regulation, and Function Plenum Press, New York, pp. 37–66.

    Google Scholar 

  6. K. Kratochwil (1987). Tissue combination and organ culture studies in the development of the embryonic mammary gland. In R. B. L. Gwatkin (ed.),Developmental Biology: A Comprehensive Synthesis Plenum Press, New York, pp. 315–334.

    Google Scholar 

  7. C. W. Daniel and G. B. Silberstein (1987). Postnatal development of the rodent mammary gland. In M. C. Neville and C. W. Daniel (eds.),The Mammary Gland Development, Regulation and Function Plenum Press, New York, pp. 3–36.

    Google Scholar 

  8. A. Raynaud (1961). Morphogenesis of the mammary gland. In S. K. Kon and A. T. Cowie (eds.),Milk: The Mammary Gland and Its Secretion Academic Press, New York, pp. 3–46.

    Google Scholar 

  9. A. Propper (1972). Rôle du mésenchyme dans la différenciation de la glande mammaire chez l'embryon de lapin.Bull. Soc. Zool. Fr. 97505–512.

    Google Scholar 

  10. B. I. Balinsky (1950). On the developmental processes in mammary glands and other epidermal structures.Trans. R. Soc. Edinb. 621–31.

    Google Scholar 

  11. A. Y. Propper (1978). Wandering epithelial cells in rabbit embryo milk line.Dev. Biol. 67225–231.

    Article  PubMed  Google Scholar 

  12. G. R. Cunha, P. Young, K. Christov, R. Guzman, S. Nandi, F. Talamantes, and G. Thordarson (1995). Mammary phenotypic expression induced in epidermal cells by embryonic mammary mesenchyme.Acta Anat. 152195–204.

    PubMed  Google Scholar 

  13. J. Taylor-Papadimitriou and E. B. Lane (1987). Keratin expression in the mammary gland. In M. C. Neville and C. W. Daniel (eds.),The Mammary Gland: Development, Regulation, and Function Plenum Press, New York, pp. 181–215.

    Google Scholar 

  14. T. Sakakura, Y. Nishizuka, and C. J. Dawe (1976). Mesenchyme-dependent morphogenesis and epithelium-specific cytodifferentiation in mouse mammary gland.Science 1941439–1441.

    PubMed  Google Scholar 

  15. G. R. Cunha, P. Young, S. Hamamoto, R. Guzman, and S. Nandi (1992). Developmental response of adult mammary epithelial cells to various fetal and neonatal mesenchymes.Epithelial Cell Biol. 1105–118.

    PubMed  Google Scholar 

  16. K. Kratochwil (1975). Experimental analysis of the prenatal development of the mammary gland.Mod. Probl. Pediat. 151–15.

    Google Scholar 

  17. R. Nusse and H. E. Varmus (1992). Wnt genes.Cell 691073–1087.

    Article  PubMed  Google Scholar 

  18. K. Kratochwil and P. Schwartz (1976). Tissue interaction in androgen response of embryonic mammary rudiment of mouse: Identification of target tissue of testosterone.Proc. Natl. Acad. Sci. USA 734041–4044.

    PubMed  Google Scholar 

  19. K. Korach (1994). Insights from the study of animals lacking functional estrogen receptor.Science 2661524–1527.

    PubMed  Google Scholar 

  20. Y. Matsui, S. A. Halter, J. T. Holt, B. L. M. Hogan, and R. J. Coffey (1990). Development of mammary hyperplasia and neoplasia in MMTV-TGFα transgenic mice.Cell 611147–1155.

    Article  PubMed  Google Scholar 

  21. C. Jhappan, C. Stahle, R. N. Harkins, N. Fausto, G. H. Smith, and G. T. Merlino (1990). TGFα overexpression in transgenic mice induces liver neoplasia and abnormal development of the mammary gland and pancreas.Cell 611137–1146.

    Article  PubMed  Google Scholar 

  22. E. P. Sandgren, N. C. Luetteke, R. D. Palmiter, R. L. Brinster, and D. C. Lee (1990). Overexpression of TGFα in transgenic mice: Induction of epithelial hyperplasia, pancreatic metaplasia, and carcinoma of the breast.Cell 611121–1135.

    Article  PubMed  Google Scholar 

  23. G. Stamp, V. Fantl, R. Poulsom, S. Jamieson, R. Smith, G. Peters, and C. Dickson (1992). Nonuniform expression of a mouse mammary tumor virus-drivenint-2/Fgf-3 transgene in pregnancy-responsive breast tumors.Cell Growth Differ. 3929–938.

    PubMed  Google Scholar 

  24. J. W. Muller, F. S. Lee, C. Dickson, G. Peters, P. Pattengale, and P. Leder (1990). Theint-2 gene product acts as an epithelial growth factor in transgenic mice.EMBO J. 9907–913.

    PubMed  Google Scholar 

  25. A. S. Tsukamoto, R. Grosschedl, R. C. Guzman, T. Parslow, and H. E. Varmus (1988). Expression of theint-1 gene in transgenic mice is associated with mammary gland hyperplasia and adenocarcinomas in male and female mice.Cell 59619–625.

    Article  Google Scholar 

  26. D. F. Pierce, Jr., M. D. Johnson, Y. Matsui, S. D. Robinson, L. I. Gold, A. F. Purchio, C. W. Daniel, B. L. Hogan, and H. L. Moses (1993). Inhibition of mammary duct development but not alveolar outgrowth during pregnancy in transgenic mice expressing active TGF-beta 1.Genes Dev. 72308–2317.

    PubMed  Google Scholar 

  27. T. P. Lin, R. C. Guzman, R. C. Osborn, G. Thordarson, and S. Nandi (1992). Role of endocrine, autocrine, and paracrine interactions in the development of mammary hyperplasia in Wnt-1 transgenic mice.Cancer Res. 524413–4419.

    PubMed  Google Scholar 

  28. K. Kratochwil (1977). Development and loss of androgen responsiveness in the embryonic rudiment of the mouse mammary gland.Dev. Biol. 61358–365.

    Article  PubMed  Google Scholar 

  29. T. Sakakura, Y. Sakagami, and Y. Nishizuka (1982). Dual origin of mesenchymal tissues participating in mouse mammary gland embryogenesis.Dev. Biol. 91202–207.

    Article  PubMed  Google Scholar 

  30. K. B. DeOme, L. J. Faulkin, Jr., and H. A. Bern (1959). Development of mammary tumors from hyperplastic alveolar nodules transplanted into gland-free mammary fat pads of female C3H mice.Cancer Res. 19515–520.

    PubMed  Google Scholar 

  31. T. Sakakura, I. Kusano, M. Kusakabe, Y. Inaguma, and Y. Nishizuka (1987). Biology of mammary fat pad in fetal mouse: Capacity to support development of various fetal epitheliain vivo.Development 100421–430.

    PubMed  Google Scholar 

  32. R. Narbaitz, W. E. Stumpf, and M. Sar (1980). Estrogen receptors in mammary gland primordia of fetal mouse.Anat. Embryol. 158161–166.

    Article  PubMed  Google Scholar 

  33. S. Z. Haslam and G. Shyamala (1981). Relative distribution of estrogen and progesterone receptors among the epithelial, adipose, and connective tissue components of the normal mammary gland.Endocrinology 108825–830.

    PubMed  Google Scholar 

  34. M. J. Bissell and H. G. Hall (1987). Form and function in the mammary gland: The role of extracellular matrix. In M. C. Neville and C. W. Daniel (eds.),The Mammary Gland: Development, Regulation, and Function Plenum Press, New York, pp. 97–146.

    Google Scholar 

  35. S. Nandi (1958). Endocrine control of mammary gland development and function in the C3H/He Crgl mouse.J. Natl. Cancer Inst. 211039–1063.

    PubMed  Google Scholar 

  36. R. L. Ceriani (1970). Fetal mammary gland differentiationin vitro in response to hormones. I. Morphological findings.Dev. Biol. 21506–529.

    Article  PubMed  Google Scholar 

  37. R. L. Ceriani (1970). Fetal mammary gland differentiationin vitro in response to hormones. II. Biochemical findings.Dev. Biol. 21530–546.

    Article  PubMed  Google Scholar 

  38. H. Nagasawa and T. Mori (1988). Long-term effects of perinatal exposure to hormones and related substances on normal and neoplastic growth of murine mammary glands. In T. Mori and H. Nagasawa (eds.),Toxicity of Hormones in Perinatal Life CRC Press, Boca Raton, Florida pp. 81–88.

    Google Scholar 

  39. S. Z. Haslam and K. A. Nummy (1992). The ontogeny and cellular distribution of estrogen receptors in normal mouse mammary gland.J. Steroid Biochem. Mol. Biol. 42589–595.

    Article  PubMed  Google Scholar 

  40. B. Mintz (1978). Genetic mosaicism andin vivo analyses of neoplasia and differentiation. In G. Saunders (ed.),Cell Differentiation and Neoplasia Raven Press, New York, pp. 27–56.

    Google Scholar 

  41. G. R. Cunha, N. Hayashi, and Y. C. Wong (1991). Regulation and growth of normal adult and neoplastic epithelial by inductive mesenchyme. In J. T. Issacs (ed.),Prostate Cancer: Cell and Molecular Mechanisms in Diagnosis and Treatment Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, pp. 73–90.

    Google Scholar 

  42. J. J. De Cosse, C. L. Gossens, J. F. Kuzma, and B. R. Unsworth (1975). Embryonic inductive tissues that cause histological differentiation of murine mammary carcinomain vitro.J. Natl. Cancer Inst. 54913–921.

    PubMed  Google Scholar 

  43. S. Sakaguchi, T. Takahashi, T. Sakakura, Y. Sakagami, Y. Nishizuka, and H. Tanaka (1981). Earlier appearance of murine mammary tumor virus-associated antigens in duct-alveolus nodules induced by transplantation of fetal salivary mesenchyme into C3H mouse mammary glands.Gann 72982–987.

    PubMed  Google Scholar 

  44. T. Sakakura (1983). Epithelial-mesenchymal interactions in mammary gland development and its perturbation in relation to tumorigenesis. In M. A. Rich, J. C. Hager, and P. Furmanski (eds.),Understanding Breast Cancer: Clinical and Laboratory Concepts Marcel Dekker, New York, pp. 261–284.

    Google Scholar 

  45. T. Sakakura, Y. Sakagami, and Y. Nishizuka (1981). Accelerated mammary cancer development by fetal salivary mesenchyme isografted to adult mouse mammary epithelium.J. Natl. Cancer Inst. 66953–959.

    PubMed  Google Scholar 

  46. G. B. Silberstein and C. W. Daniel (1987). Reversible inhibition of mammary gland growth by transforming growth factor-beta.Science 237291–293.

    PubMed  Google Scholar 

  47. C. W. Daniel and S. D. Robinson (1992). Regulation of mammary growth and function by TGF-beta.Mol. Reprod. Dev. 32145–151.

    Article  PubMed  Google Scholar 

  48. S. P. Ethier and R. M. Van de Velde (1990). Secretion of a TGF-β-like growth inhibitor by normal rat mammary epithelial cellsin vitro.J. Cell. Physiol. 14215–20.

    Article  PubMed  Google Scholar 

  49. C. Knabbe, M. E. Lippman, L. M. Wakefield, K. C. Flanders, A. Kasid, R. Derynck, and R. B. Dickson (1987). Evidence that transforming growth factor-beta is a hormonally regulated negative growth factor in human breast cancer cells.Cell 48417–428.

    Article  PubMed  Google Scholar 

  50. C. W. Daniel, G. B. Silberstein, K. Van Horn, P. Strickland, and S. Robinson (1989). TGF-β1-Induced inhibition of mouse mammary ductal growth: Developmental specificity and characterization.Dev. Biol. 13520–30.

    Article  PubMed  Google Scholar 

  51. S. D. Robinson, G. B. Silberstein, A. B. Roberts, K. C. Flanders, and C. W. Daniel (1991). Regulated expression and growth inhibitory effects of transforming growth factor-β isoforms in mouse mammary gland development.Development 113867–878.

    PubMed  Google Scholar 

  52. G. B. Silberstein, S. Strickland, S. Coleman, and C. W. Daniel (1990). Epithelium-dependent extracellular matrix synthesis in transforming growth factor-beta 1-growth-inhibited mouse mammary gland.J. Cell Biol. 1102209–2219.

    PubMed  Google Scholar 

  53. 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-beta 1.Dev. Biol. 152354–362.

    Article  PubMed  Google Scholar 

  54. S. D. Robinson, A. B. Roberts, and C. W. Daniel (1993). TGF beta suppresses casein synthesis in mouse mammary explants and may play a role in controlling milk levels during pregnancy.J. Cell Biol. 120245–251.

    PubMed  Google Scholar 

  55. A. W. Sudlow, C. J. Wilde, and R. D. Burgoyne (1994). Transforming growth factor-beta 1 inhibits casein secretion from differentiating mammary-gland explants but not from lactating mammary cells.Biochem J. 304333–336.

    PubMed  Google Scholar 

  56. T. Yamamoto, H. Komura, K. Morishige, C. Tadokoro, M. Sakata, H. Kurachi, and A. Miyake (1994). Involvement of autocrine mechanism of transforming growth factor-beta in the functional differentiation of pregnant mouse mammary gland.Eur. J. Endocrinol. 130302–307.

    PubMed  Google Scholar 

  57. M. Mieth, F. D. Boehmer, R. Ball, B. Groner, and R. Grosse (1990). Transforming growth factor-beta inhibits lactogenic hormone induction of beta-casein expression in HC11 mouse mammary epithelial cells.Growth Factors 49–15.

    PubMed  Google Scholar 

  58. C. Jhappan, A. G. Geiser, E. C. Kordon, D. Bagheri, L. Hennighausen, A. B. Roberts, G. H. Smith, and G. Merlino (1993). Targeting expression of a transforming growth factor beta 1 transgene to the pregnant mammary gland inhibits alveolar development and lactation.EMBO J. 121835–1845.

    PubMed  Google Scholar 

  59. D. S. Liscia, G. Merlo, F. Ciardiello, N. Kim, G. H. Smith, R. Callahan, and D. S. Salomon (1990). Transforming growth factor-alpha messenger RNA localization in the developing adult rat and human mammary gland byin situ hybridization.Dev. Biol. 140123–131.

    Article  PubMed  Google Scholar 

  60. S. M. Snedeker, C. F. Brown, and R. P. DiAugustine (1991). Expression and functional properties of transforming growth factor α and epidermal growth factor during mouse mammary gland ductal morphogenesis.Proc. Natl. Acad. Sci. USA 88276–280.

    PubMed  Google Scholar 

  61. E. M. Valverius, S. E. Bates, M. R. Stampfer, R. Clark, F. McCormick, D. S. Salomon, M. E. Lippman, and R. B. Dickson (1989). Transforming growth factor alpha production and epidermal growth factor receptor expression in normal and oncogene transformed human mammary epithelial cells.Mol. Endocrinol 3203–214.

    PubMed  Google Scholar 

  62. W. Imagawa, G. K. Bandyopadhyay, and S. Nandi (1990). Regulation of mammary epithelial cell growth in mice and rats.Endocrine Rev. 11494–523.

    Google Scholar 

  63. B. K. Vonderhaar (1987). Local effects of EGF, alpha-TGF, and EGF-like growth factors on lobuloalveolar development of the mouse mammary glandin vivo.J. Cell. Physiol. 132581–584.

    Article  PubMed  Google Scholar 

  64. R. J. Coffey, Jr., K. S. Meise, Y. Matsui, B. L. Hogan, P. J. Dempsey, and S. A. Halter (1994). Acceleration of mammary neoplasia in transforming growth factor alpha transgenic mice by 7,12-dimethylbenzanthracene.Cancer Res. 541678–1683.

    PubMed  Google Scholar 

  65. S. A. Halter, P. Dempsey, Y. Matsui, M. K. Stokes, D. R. Graves, B. L. Hogan, and R. J. Coffey (1992). Distinctive patterns of hyperplasia in transgenic mice with mouse mammary tumor virus transforming growth factor-alpha. Characterization of mammary gland and skin proliferations.Am. J. Pathol. 1401131–1146.

    PubMed  Google Scholar 

  66. S. Sakai, M. Mizuno, T. Harigaya, K. Yamamoto, T. Mori, R. J. Coffey, and H. Nagasawa (1994). Cause of failure of lactation in mouse mammary tumor virus/human transforming growth factor alpha transgenic mice.Proc. Soc. Exp. Biol. Med. 205236–242.

    PubMed  Google Scholar 

  67. S. A. Aaronson, J. S. Rubin, P. W. Finch, J. Wong, C. Marchese, J. Falco, W. G. Taylor, and M. H. Kraus (1990). Growth factor-regulated pathways in epithelial cell proliferation.Am. Rev. Respir. Dis. 142S7–10.

    PubMed  Google Scholar 

  68. W. Imagawa, G. R. Cunha, P. Young, and S. Nandi (1994). Keratinocyte growth factor and acidic fibroblast growth factor are mitogens for primary cultures of mammary epithelium.Biochem. Biophys. Res. Commun. 2041165–1169.

    Article  PubMed  Google Scholar 

  69. T. R. Ulich, E. S. Yi, R. Cardiff, S. Yin, N. Bikhazi, R. Biltz, C. F. Morris, and G. F. Pierce (1994). Keratinocyte growth factor is a growth factor for mammary epitheliumin vivo. The mammary epithelium of lactating rats is resistant to the proliferative action of keratinocyte growth factor.Am. J. Pathol. 144862–868.

    PubMed  Google Scholar 

  70. E. S. Yi, A. A. Bedoya, H. Lee, S. Kim, R. M. Housley, S. L. Aukerman, J. E. Tarpley, C. Starnes, C. Starnes, S. Yin, G. F. Pierce,et al. (1994). Keratinocyte growth factor causes cystic dilation of the mammary glands of mice. Interactions of keratinocyte growth factor, estrogen, and progesteronein vivo.Am. J. Pathol. 1451015–1022.

    PubMed  Google Scholar 

  71. T. R. Ulich, E. S. Yi, K. Longmuir, S. Yin, R. Biltz, C. F. Morris, R. M. Housley, and G. F. Pierce (1994). Keratinocyte growth factor is a growth factor for type II pneumocytesin vivo.J. Clin. Invest. 931298–1306.

    PubMed  Google Scholar 

  72. P. W. Finch, G. R. Cunha, J. S. Rubin, J. Wong, and D. Ron (1995). Pattern of KGF and KGFR expression during mouse fetal development suggests a role in mediating morphogenetic mesenchymal-epithelial interactions.Dev. Dynam. (in press).

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Cunha, G.R., Hom, Y.K. Role of mesenchymal-epithelial interactions in mammary gland development. J Mammary Gland Biol Neoplasia 1, 21–35 (1996). https://doi.org/10.1007/BF02096300

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