The Role of Mammary Stroma in Modulating the Proliferative Response to Ovarian Hormones in the Normal Mammary Gland

  • Terry L. Woodward
  • Jian Wei Xie
  • Sandra Z. Haslam


Postnatal mammary gland development is highlydependent on the ovarian steroids, estrogen andprogesterone. However, evidence from both in vitro andin vivo studies indicates that steroid-induceddevelopment occurs indirectly, requiring stromalcooperation in epithelial proliferation andmorphogenesis. Stromal cells appear to influenceepithelial cell behavior by secretion of growth factorsand/or by altering the composition of the extracellular matrix inwhich epithelial cells reside. This review will discussthe requirement for stromal tissue in modulatingproliferative responses to ovarian hormones during postnatal development and the potential role ofthe EGF, IGF, HGF and FGF3 growth factorfamilies. Additionally, the roles of extracellularmatrix proteins, including fibronectin, collagens andlaminin, will be summarized.



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  1. 1.
    C. Birchmeier and W. Birchmeier (1993). Molecular aspects of mesenchymal-epithelial interactions. Ann. Rev. Cell Biol. 9: 511-540.Google Scholar
  2. 2.
    K. Kratochwil (1969). Organ specificity in mesenchymal induction demonstrated in the embryonic development of the mammary gland of the mouse. Devel. Biol. 20: 46-71.Google Scholar
  3. 3.
    G. R. Cunha and Y. K. Hom (1996). Role of mesenchymal-epithelial interactions in mammary gland development. J. Mam. Gland Biol. Neoplasia 1: 21-35.Google Scholar
  4. 4.
    S. Z. Haslam (1986). Mammary fibroblast influence on normal mouse mammary epithelial cell responses to estrogen in vitro. Cancer Res. 46: 310-316.Google Scholar
  5. 5.
    S. Z. Haslam and L. J. Counterman (1991). Mammary stroma modulates hormonal responsiveness of mammary epithelium in vivo in the mouse. Endocrinology 129: 2017-2023.Google Scholar
  6. 6.
    C.M. McGrath (1983). Augmentation of the response of normal mammary epithelial cells to estradiol by mammary stroma. Cancer Res. 43: 1355-1360.Google Scholar
  7. 7.
    J. L. Fendrick, A. M. Raafat, and S. Z. Haslam (1998). Mammary gland growth and development from the postnatal period to postmenopause: ovarian steroid receptor ontogeny and regulation in the mouse. J. Mam. Gland Biol. Neoplasia 4 (in press).Google Scholar
  8. 8.
    S. Z. Haslam (1989). The ontogeny of mouse mammary gland responsiveness to ovarian steroid hormones. Endocrinology 125: 2766-2772.Google Scholar
  9. 9.
    K. S. McCarty, Jr., E. Szabo, J. L. Flowers, E. B. Cox, G. S. Leight, L. Miller, J. Konrath, J. T. Soper, D. A. Budwit, W. T. Creasman, H. F. Seigler, and K. S. McCarty, Sr. (1986). Use of amonoclonal anti-estrogen receptor antibody in the immuno-histochemical evaluation of human tumors. Cancer Res. (Suppl.) 46: 4244s-4248s.Google Scholar
  10. 10.
    C. Malet, A. Gompel, H. Yaneva, H. Cren, N. Fidji, I. Mowszowicz, F. Kuttenn, and P. Mauvais-Jarvis (1991). Estradiol and progesterone receptors in cultured normal human breast epithelial cells and fibroblasts: Immunocytochemical studies. J. Clin. Endocrinol. Metabol. 73: 8-17.Google Scholar
  11. 11.
    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 108: 825-830.Google Scholar
  12. 12.
    C.W. Daniel, G. B. Silberstein, and P. Strickland (1987). Direct action of 17 beta-estradiol on mouse mammary ducts analyzed by sustained release implants and steroid autoradiography. Cancer Res. 47: 6052-6057.Google Scholar
  13. 13.
    S. Z. Haslam (1988). Local versus systemically mediated effects of estrogen on normal mammary epithelial cell deoxyribonucleic acid synthesis. Endocrinology 122: 860-867.Google Scholar
  14. 14.
    W. Imagawa, J. Yang, R. Guzman, and S. Nandi (1994). Control of mammary gland development. In E. Knobil and J. D. Neill (eds.), The Physiology of Reproduction Second Edition, Raven Press, Ltd., New York, pp. 1033-1063.Google Scholar
  15. 15.
    J. Xie and S. Z. Haslam (1997). Extracellular matrix regulates ovarian hormone-dependent proliferation of mouse mammary epithelial cells. Endocrinology 138: 2466-2473.Google Scholar
  16. 16.
    W. P. Bocchinfuso and K. S. Korach (1997). Mammary gland development and tumorigenesis in estrogen receptor knockout mice. J. Mam. Gland Biol. Neoplasia 2: 323-334.Google Scholar
  17. 17.
    G. R. Cunha, P. Young, Y. K. Hom, P. S. Cooke, J. A. Taylor, and D. B. Lubahn (1997). Elucidation of a role for stromal steroid hormone receptors in mammary gland growth and development using tissue recombination experiments. J. Mam. Gland Biol. Neoplasia 2: 393-402.Google Scholar
  18. 18.
    K. Hoshino. (1978). Mammary transplantation and its histogenesis in mice. In A. Yokoyama, M. Mizuno and H. Nagasawa (eds.), Physiology of Mammary Glands University Park Press, University Park, Maryland, pp. 163-228.Google Scholar
  19. 19.
    C. W. Daniel, J. J. Berger, P. Strickland, and R. Garcia. (1984). Similar growth pattern of mouse mammary cells cultivated in collagen matrix in vivo and in vitro. Devel. Biol. 104: 57-64.Google Scholar
  20. 20.
    B. E. Elliot, S. P. Tam, D. Dexter, and Z. Q. Chen (1992). Capacity of adipose tissue to promote growth and metastasis of amurine mammary carcinoma: effect of estrogen and progesterone. Int. J. Cancer 51: 416-424.Google Scholar
  21. 21.
    G. Shyamala and A. Ferenczy (1984). Mammary fat pad may be a potential site for initiation of estrogen action in normal mouse mammary glands. Endocrinology 115: 1078-1081.Google Scholar
  22. 22.
    T. L. Woodward, W. E. Beale, and R. M. Akers (1993). Cell interactions in initiation of mammary epithelial proliferation by oestradiol and progesterone in prepubertal heifers. J. Endocrinol. 136: 149-157.Google Scholar
  23. 23.
    J. J. Berger and C. W. Daniel (1983). Stromal DNA synthesis is stimulated in young, but not serially aged, mouse mammary epithelium. Mech. Aging Devel. 2: 259-264.Google Scholar
  24. 24.
    S. Z. Haslam (1988). Cell to cell interactions and normal mammary gland function. J. Dairy Sci. 71: 2843-2854.Google Scholar
  25. 25.
    S. Z. Haslam, L. J. Counterman, and A. R. St. John (1993). Hormonal basis for acquisition of estrogen-dependent progesterone receptors in the normal mouse mammary gland. Steroid Biochem. 12: 27-34.Google Scholar
  26. 26.
    J. Barlow, T. Casey, J-F Chiu, and K. Plaut (1997). Estrogen affects development of alveolar structures in whole-organ culture of mouse mammary glands. Biochem. Biophys. Res. Commun. 232: 340-344.Google Scholar
  27. 27.
    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. U. S. A. 88: 276-280.Google Scholar
  28. 28.
    D. P. Ankrapp, J. M. Bennett, and S. Z. Haslam (1998). The role of epidermal growth factor in the acquisition of ovarian steroid hormone responsiveness in the normal mouse mammary gland. J. Cell Physiol. 174: 251-260.Google Scholar
  29. 29.
    S. Coleman, G. B. Silberstein, and C. W. Daniel (1988). Ductal morphogenesis in the mouse mammary gland: evidence supporting a role for epidermal growth factor. Devel. Biol. 127: 304-315.Google Scholar
  30. 30.
    B. K. Vonderhaar (1987). Local effects of EGF, α-TGF, and EGF-like growth factors on lobuloalveolar development of the mouse mammary gland in vivo. J. Cell. Physiol. 132: 581-584.Google Scholar
  31. 31.
    S. Z. Haslam, L. J. Counterman, and K. A. Nummy (1993). Effects of epidermal growth factor, estrogen and progestin on DNA synthesis in mammary cells in vivo are determined by the developmental state of the gland. J. Cell. Physiol. 155: 72-78.Google Scholar
  32. 32.
    S. Z. Haslam, L. J. Counterman, and K. A. Nummy (1992). EGF receptor regulation in normal mouse mammary gland. J. Cell. Physiol. 152: 553-557.Google Scholar
  33. 33.
    J. I. Jones and D. R. Clemmons (1995). Insulin-like growth factors and their binding proteins: Biological actions. Endoticrine Rev. 16: 3-34.Google Scholar
  34. 34.
    D. Yee, S. Paik, G. S. Lebovic, R. R. Marcus, R. E. Favoni, K. J. Cullen, M. E. Lippman, and N. Rosen (1989). Analysis of insulin-like growth factor I gene expression in malignancy: evidence for a paracrine role in human breast cancer. Mol. Endocrinol. 3: 509-517.Google Scholar
  35. 35.
    S. D. Hauser, M. F. McGrath, R. J. Collier, and G. G. Krivi (1990). Cloning and in vivo expression of bovine growth hormone receptor mRNA. Mol. Cell Endocrinol. 72: 187-200.Google Scholar
  36. 36.
    W. Ruan, V. Catanese, R. Wieczorek, M. Feldman, and D. L. Kleinberg (1995). Estradiol enhances the stimulatory effect of insulin-like growth factor-I (IGF-I) on mammary development and growth hormone-induced IGF-I messenger ribonucleic acid. Endocrinology 136: 1296-1302.Google Scholar
  37. 37.
    K. Swisshelm, K. Ryan, K. Tsuchiya, and R. Sager (1995). Enhanced expression of an insulin growth factor-like binding protein (mac25) in senescent human mammary epithelial cells and induced expression with retinoic acid. Proc. Natl. Acad. Sci. U. S. A. 92: 4472-4476.Google Scholar
  38. 38.
    H. Huynh, X. F. Yang, and M. Pollak (1996). A role for insulin-like growth factor binding protein 5 in the antiproliferative action of the antiestrogen ICI 182780. Cell Growth Differ. 7: 1501-1506.Google Scholar
  39. 39.
    H. Huynh, X. Yang, and M. Pollak (1996). Estradiol and antiestrogens regulate a growth inhibitory insulin-like growth factor binding protein 3 autocrine loop in human breast cancer cells. J. Biol. Chem. 271: 1016-1021.Google Scholar
  40. 40.
    R. B. Clarke, A. Howell, and E. Anderson (1997). Type I insulin-like growth factor receptor gene expression in normal human breast tissue treated with oestrogen or progesterone. Brit. J. Cancer 75: 251-257.Google Scholar
  41. 41.
    M. S. Pepper, J. V. Soriano, P. A. Menoud, A. P. Sappino, L. Orci, and R. Montesano (1995). Modulation of hepatocyte growth factor and c-Met in the rat mammary gland during pregnancy lactation and involution. Exp. Cell Res. 219: 204-210.Google Scholar
  42. 42.
    B. Niranjan, L. Buluwela, J. Yant, N. Perusinghe, A. Atherton, D. Phippard, T. Dale, B. Gusterson, and T. Kamalati (1995). HGF/SF: a potent cytokine for mammary growth, morphogenesis and development. Development 121: 2897-2908.Google Scholar
  43. 43.
    Y. Yang, E. Spitzer, D. Meyer, M. Sachs, C. Neimann, G. Hartmann, K. M. Weidner, C. Birchmeier, and W. Birchmeier (1995). Sequential requirement of hepatocyte growth factor and neuregulin in the morphogenesis and differentiation of the mammary gland. J. Cell Biol. 131: 215-226.Google Scholar
  44. 44.
    J. V. Soriano, M. S. Pepper, L. Orci, and R. Montessano (1998). Roles of hepatocyte growth factor/scatter factor and transforming growth factor-β1 in mammary ductal morphogenesis. J. Mam. Gland Biol. Neoplasia 3: 133-150.Google Scholar
  45. 45.
    N. Rahimi, R. Saulnier, T. Nakamura, M. Park, and B. Elliott (1994). Role of hepatocyte growth factor in breast cancer: a novel mitogenic factor secreted by adipocytes. DNA Cell Biol. 13: 1189-1197.Google Scholar
  46. 46.
    Y. Liu, L. Lin, and R. Zarnegar (1994). Modulation of hepatocyte growth factor gene expression by estrogen in the mouse ovary. Mol. Cell. Endocrinol. 104: 173-181.Google Scholar
  47. 47.
    Y. Liu, G. K. Michalopoulos, and R. Zarnegar (1994). Structural and functional characterization of the mouse hepatocyte growth factor gene promoter. J. Biol. Chem. 269: 4152-4160.Google Scholar
  48. 48.
    J. V. Soriano, M. S. Pepper, T. Nakamura, L. Orci, and R. Montesano (1995). Hepatocyte growth factor stimulates extensive development of branching duct-like structures by cloned mammary gland epithelial cells. J. Cell Sci. 108: 413-430.Google Scholar
  49. 49.
    D. Givol and A. Yayon (1992). Complexity of FGF receptors: genetic basis for structural diversity and functional specificity. FASEB J. 6: 3362-3369.Google Scholar
  50. 50.
    S. Coleman-Krnacik and J. M. Rosen (1994). Differential temporal and spatial gene expression of fibroblast growth factor family members during mouse mammary gland development. Mol. Endocrinol. 8: 218-229.Google Scholar
  51. 51.
    G. D. Shipley, W. W. Keeble, J. E. Hendrickson, R. J. Coffey, Jr., and M. R. Pittelkow (1989). Growth of normal human keratinocytes and fibroblasts in serum-free medium is stimulated by acidic and basic fibroblast growth factor. J. Cell Physiol. 138: 511-518.Google Scholar
  52. 52.
    L. Ronnov-Jessen and O. W. Petersen (1993). Induction of alpha-smooth muscle actin by transforming growth factor-beta 1 in quiescent human breast gland fibroblasts. Implications for myofibroblast generation in breast neoplasia. Lab. Invest. 68: 696-707.Google Scholar
  53. 53.
    A. Johns, A. D. Freay, W. Fraser, K. S. Korach, and G. M. Rubanyi (1996). Disruption of estrogen receptor gene prevents 17 beta estradiol-induced angiogenesis in transgenic mice. Endocrinology 137: 4511-4513.Google Scholar
  54. 54.
    J. Fujimoto, M. Hori, S. Ichigo, and T. Tamaya (1996). Expression of basic fibroblast growth factor and its mRNA in uterine endometrium during the menstrual cycle. Gynecol. Endocrinol. 10: 193-197.Google Scholar
  55. 55.
    J. Fujimoto, M. Hori, S. Ichigo, and T. Tamaya (1997). Ovarian steroids regulate the expression of basic fibroblast growth factor and its mRNA in fibroblasts derived from uterine endometrium. Ann. Clin. Biochem. 34: 91-96.Google Scholar
  56. 56.
    M.M. Zutter, H. Sun, and S. A. Santoro (1998). Altered integrin expression and the malignant phenotype: the contribution of multiple integrated integrin-receptors. J. Mam. Gland Biol. Neoplasia 3: 191-200.Google Scholar
  57. 57.
    C. H. Streuli and G. Edwards (1998). Control of normal mammary epithelial phenotype by integrins. J. Mam. Gland Biol. Neoplasia 3: 151-164.Google Scholar
  58. 58.
    C. H. Streuli, C. Schmidhauser, N. Bailey, P. Yurchenco, A. P. N. Skubitz, C. Roskelley, and M. J. Bissell (1995). Laminin mediates tissue-specific gene expression in mammary epithelia. J. Cell Biol. 129: 591-603.Google Scholar
  59. 59.
    A. R. Howlett and M. J. Bissell (1993). The influence of tissue microenvironment (stroma and extracellular matrix) on the development and function of mammary epithelium. Epith. Cell Biol. 2: 79-89.Google Scholar
  60. 60.
    P. J. Keely, J. E. Wu, and S. A. Santoro (1995). The spatial and temporal expression of the α2 β1 integrin and its ligands, collagen I, collagen IV, and laminin, suggests important roles in mouse mammary morphogenesis. Differentiation 59: 1-13.Google Scholar
  61. 61.
    M. S. Wicha (1984). Interaction of rat mammary epithelium with extracellular matrix components. Prog. Clin. Biol. Res. 145: 129-142.Google Scholar
  62. 62.
    G. Parry, B. Cullen, C. S. Kaetzel, R. Kramer, and L. Moss (1987). Regulation of differentiation and polarized secretion in mammary epithelial cells maintained in culture: extracellular matrix and membrane polarity influences. J. Cell Biol. 105: 2043-2051.Google Scholar
  63. 63.
    C. H. Streuli and M. J. Bissell (1990). Expression of extracellular matrix components is regulated by substratum. J. Cell Biol. 110: 1405-1415.Google Scholar
  64. 64.
    P. Simon-Assmann, F. Bouziges, C. Arnold, K. Haffen, and M. Kedinger (1988). Epithelial-mesenchymal interactions in the production of basement membrane components in the gut. Development 102: 339-347.Google Scholar
  65. 65.
    F. Berdichevsky, D. Alford, B. D'Souza, and J. Taylor-Papadimitriou (1994). Branching morphogenesis of human mammary epithelial cells in collagen gels. J. Cell Sci. 107: 3557-3568.Google Scholar
  66. 66.
    M. L. Li, J. Aggeler, D. A. Farson, C. Hatier, J. Hassell, and M. J. Bissell (1987). Influence of a reconstituted basement membrane and its components on casein gene expression and secretion in mouse mammary epithelial cells. Proc. Natl. Acad. Sci. U.S.A. 84: 136-140.Google Scholar
  67. 67.
    S. Stahl, S. Weitzman, and J. C. R. Jones (1997). The role of laminin-5 and its receptor in mammary epithelial cell branching morphogenesis. J. Cell. Sci. 110: 55-63.Google Scholar
  68. 68.
    B. Elliot, A. Ostman, B. Westermark, and K. Rubin (1992). Modulation of growth factor responsiveness of murine mammary carcinoma cells by cell matrix interactions: correlation of cell proliferation and spreading. J. Cell. Physiol. 152: 292-301.Google Scholar
  69. 69.
    R.O. Hynes (1994). Genetic analyses of cell-matrix interactions in development. Curr. Opin. Genet. Devel. 4: 569-574.Google Scholar
  70. 70.
    K. K. Wary, F. Mainiero, S. J. Isakoff, E. E. Marcantonio, and F. G. Giancotti (1996). The adapter protein Shc couples a class of integrins to the control of cell cycle progression. Cell 87: 733-743.Google Scholar

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© Plenum Publishing Corporation 1998

Authors and Affiliations

  • Terry L. Woodward
  • Jian Wei Xie
  • Sandra Z. Haslam

There are no affiliations available

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