Abstract
The use of tissue recombinants in conjunction with steroid receptor deficient mice is described as a tool to dissect the complex paracrine pathways of sex-hormone-regulated epithelial growth and ductal morphogenesis in the mammary gland and other hormone target organs. The basic methodology involves the construction of the four possible tissue recombinants composed of epithelium (E)6 and stroma (S) from wild-type (wt) and knock-out (KO) mice: wt-S + wt-S, wt-S + KO-E, KO-S + KO-E, and KO-S + wt-E. All tissue recombinants are grown as subrenal capsule grafts in nude mice. Following appropriate hormonal challenge epithelial growth can be studied in the four types of tissue recombinants. Such studies using estrogen receptor, androgen receptor and progesterone receptor knockout mice demonstrate that epithelial steroid receptors are neither necessary nor sufficient for hormonal regulation of epithelial proliferation. Instead, hormonal regulation of epithelial proliferation is a paracrine event mediated by hormone-receptor-positive stromal cells.
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REFERENCES
S. Ohno (1979). Major Sex Determining Genes, Springer-Verlag, New York.
D. B. Lubahn, D. R. Joseph, P. M. Sullivan, H. F. Willard, F. S. French and E. M. Wilson (1988). Cloning of human androgen receptor complementary DNA and localization to the X chromosome. Science 240:327–330.
C. S. Chang, J. Kokontis, and S. T. Liao (1988). Molecular cloning of human and rat complementary DNA encoding androgen receptors. Science 240:324–326.
F. S. French, D. B. Lubahn, T. R. Brown, J. A. Simental, C. A. Quigley, W. G. Yarbrough, J. A. Tan, M. Sar, D. R. Joseph, and B. A. Evans (1990). Molecular basis of androgen insensitivity. Rec. Prog. Horm. Res. 46:1–38.
W. W. He, C. Y.-F. Young, and D. J. Tindall (1990). The molecular basis of the mouse testicular feminization (Tfm) mutation: A frame-shift mutation. Endocrinol. Suppl. 126:240.
D. B. Lubahn, J. S. Moyer, T. S. Golding, J. F. Couse, K. S. Korach, and O. Smithies (1993). Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene. Proc. Natl. Acad. Sci. U.S.A. 90:11162–11166.
J. P. Lydon, F. J. DeMayo, C. R. Funk, S. K. Mani, A. R. Hughes, C. A. Montgomery, G. Shyamala, O. M. Conneely, and B. W. O'Malley (1995). Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities. Genes Devel. 9:2266–2278.
K. Korach (1994). Insights from the study of animals lacking functional estrogen receptor. Science 266:1524–1527.
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. U.S.A. 73:4041–4044.
B. Heuberger, I. Fitzka, G. Wasner, and K. Kratochwil (1982). Induction of androgen receptor formation by epithelium-mesenchyme interaction in embryonic mouse mammary gland. Proc. Natl. Acad. Sci. U.S.A. 79:2957–2961.
H. Durnberger, B. Heuberger, P. Schwartz, G. Wasner, and K. Kratochwil (1978). Mesenchyme-mediated effect of testosterone on embryonic mammary epithelium. Cancer Res. 38:4066–4070.
H. Dürnberger and K. Kratochwil (1980). Specificity of tissue interaction and origin of mesenchymal cells in the androgen response of the embryonic mammary gland. Cell 19:465–471.
G. Wasner, I. Hennermann, and K. Kratochwil (1983). Ontogeny of mesenchymal androgen receptors in the embryonic mouse mammary gland. Endocrinology 113:1771–1780.
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.
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. 152:195–204.
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. 8:338–363.
G. R. Cunha and P. Young (1991). Inability of Tfm (testicular feminization) epithelial cells to express androgen-dependent seminal vesicle secretory proteins in chimeric tissue recombinants. Endocrinology 128:3293–3298.
G. R. Cunha, E. T. Alarid, T. Turner, A. A. Donjacour, E. L. Boutin, and B. A. Foster (1992). Normal and abnormal development of the male urogenital tract: Role of androgens, mesenchymal-epithelial interactions and growth factors. J. Androl. 13:465–475.
J. H. Clark and E. J. Peck (1979). Female Sex Steroids: Receptors and Function. Springer-Verlag, New York.
S. A. McCormack and S. R. Glasser (1980). Differential response of individual uterine cell types from immature rats treated with estradiol. Endocrinology 106:1634–1649.
W. Stumpf and M. Sar (1976). Autoradiographic localization of estrogen, androgen, progestin, and glucocorticosteroid in “target tissues” and “non-target tissues”. In J. Pasqualini (ed.), Receptors and Mechanism of Action of Steroid Hormones, Marcel Dekker Inc., New York, pp. 41–84.
M. C. McClellan, N. B. West, D. E. Tacha, G. L. Greene, and R. M. Brenner (1984). Immunocytochemical localization of estrogen receptors in the macaque reproductive tract with monoclonal antiestrophilins. Endocrinology 114:2002–2014.
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. 42:589–595.
M. Edery, M. McGrath, L. Larson, and S. Nandi (1984). Correlation between in vitro growth and regulation of estrogen and progesterone receptors in rat mammary epithelial cells. Endocrinology 115:1691–1697.
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.
G. R. Cunha, J. M. Shannon, K. D. Vanderslice, M. Sekkingstad, and S. J. Robboy (1982). Autoradiographic analysis of nuclear estrogen binding sites during postnatal development of the genital tract of female mice. J. Steroid Biochem. 17:281–286.
R. M. Bigsby and G. R. Cunha (1986). Estrogen stimulation of deoxyribonucleic acid synthesis in uterine epithelial cells which lack estrogen receptors. Endocrinology 119:390–396.
S. Yamashita, R. R. Newbold, J. A. McLachlan, and K. S. Korach (1990). The role of the estrogen receptor in uterine epithelial proliferation and cytodifferentiation in neonatal mice. Endocrinology 127:2456–2463.
M. C. McClellan, S. Rankin, N. B. West, and R. M. Brenner (1990). Estrogen receptors, progesterone receptors and DNA synthesis in the macaque endometrium during the luteal-follicular transition. J. Steroid Biochem. Mol. Biol. 37:631–641.
W. Imagawa, G. K. Bandyopadhyay, and S. Nandi (1990). Regulation of mammary epithelial cell growth in mice and rats. Endocrine Rev. 11: 494–523.
V. Casimiri, N. C. Rath, H. Parvez, and A. Psychoyos (1980). Effect of sex steroids on rat endometrial epithelium and stroma cultured separately. J. Steroid Biochem. 12:293–298.
T. Iguchi, F. D. A. Uchima, P. L. Ostrander, and H. A. Bern (1983). Growth of normal mouse vaginal epithelial cells in and on collagen gels. Proc. Natl. Acad. Sci. U.S.A. 80:3743–3747.
T. Iguchi, F.-D. A. Uchima, P. L. Ostrander, S. T. Hamamoto, and H. A. Bern (1985). Proliferation of normal mouse uterine luminal epithelial cells in serum-free collagen gel culture. Proc. Jpn. Acad. 61:292–295.
J. Julian, D. D. Carson, and S. R. Glasser (1992). Polarized rat uterine epithelium in vitro: Responses to estrogen in defined medium. Endocrinology 130:68–78.
P. S. Cooke, F.-D. A. Uchima, D. K. Fujii, H. A. Bern, and G. R. Cunha (1986). Restoration of normal morphology and estrogen responsiveness in cultured vaginal and uterine epithelia transplanted with stroma. Proc. Natl. Acad. Sci. U.S.A. 83:2109–2113.
T. Inaba, W. G. Wiest, R. C. Strickler, and J. Mori (1988). Augmentation of the response of mouse uterine epithelial cells to estradiol by uterine stroma. Endocrinology 123:1253–1258.
C. M. McGrath (1983). Augmentation of response of normal mammary epithelial cells to estradiol by mammary stroma. Cancer Res. 43:1355–1360.
S. Z. Haslam (1986). Mammary fibroblast influence on normal mouse mammary epithelial cell responses to estrogen in vitro. Cancer Res. 45:310–316.
P. Cooke, D. Buchanan, P. Young, T. Setiawan, J. Brody, K. Korach, J. Taylor, D. Lubahn, and G. Cunha (1997). Stromal estrogen receptors (ER) mediate mitogenic effects of estradiol on uterine epithelium. Proc. Natl. Acad. Sci. U.S.A. 94:6535–6540.
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. 19:515–520.
R. C. Humphreys, J. Lydon, B. W. O'Malley, and J. M. Rosen (1997). Use of PRKO mice to study the role of progesterone in mammary gland development. J. Mam. Gland Biol. Neoplasia 2(4):343–354.
C. W. Daniel, J. M. Shannon, and G. R. Cunha (1983). Transplanted mammary epithelium grows in association with host stroma: aging of serially transplanted mammary gland is intrinsic to epithelial cells. Mech. Aging Devel. 23:259–264.
L. Martin, R. Das, and C. Finn (1973). The inhibition by progesterone of uterine epithelial proliferation in the mouse. J. Endocrinol 57:549.
A. A. Donjacour, and G. R. Cunha (1993). Assessment of prostatic protein secretion in tissue recombinants made of urogenital sinus mesenchyme and urothelium from normal or androgen-insensitive mice. Endocrinology 131:2342–2350.
T. Setiawan, D. Buchanan, J. Taylor, P. Young, D. Lubahn, G. Cunha, and P. Cooke (1997). Role of stromal and epithelial estrogen receptors (ER) in uterine epithelial secretory protein production. Biol. Reprod. 56(Suppl.1):83.
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Cunha, G.R., Young, P., Hom, Y.K. et al. Elucidation of a Role for Stromal Steroid Hormone Receptors in Mammary Gland Growth and Development Using Tissue Recombinants. J Mammary Gland Biol Neoplasia 2, 393–402 (1997). https://doi.org/10.1023/A:1026303630843
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DOI: https://doi.org/10.1023/A:1026303630843