The Breast as a Developing Organ

  • Jose Russo
  • Irma H. Russo


The breast is a bilateral organ that in the female undergoes dramatic changes in size, shape, and function in association with infantile growth, puberty, pregnancy, lactation, and post-menopausal regression [1, 2, 3, 4]. The fact that the breast is the source of the most frequently diagnosed malignancy in the female population [5,6] requires to fully understand how the various phases of development are influenced by endocrinological and reproductive events, because they will ultimately determine the risk of developing breast cancer [3,4,7].


Breast Cancer Mammary Gland Nulliparous Woman Parous Woman Human Breast Epithelial Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Tanner, J.M. (Ed) The development of the reproductive system. In: Growth at Adolescence, Blackwell Scientific, Oxford, UK, pp 28–39, 1962.Google Scholar
  2. 2.
    Vorherr, H. (Ed) Development of the female breast. In: The Breast, Academic Press, New York, pp. 1–18, 1974.Google Scholar
  3. 3.
    Russo, J. and Russo, I.H. In: The Mammary Gland (Neville, M.C. and Daniel, C.W. Eds), Plenum Publishing Corporation, New York, NY. pp 67–93, 1987.Google Scholar
  4. 4.
    Russo, I.H., and Russo, J. Mammary gland neoplasia in long-term rodent studies. Environ. Health Perspect. 104: 938–967, 1996.CrossRefGoogle Scholar
  5. 5.
    Jemal, A., Murray, T., Samuels, A., Ghafoor, A., Ward, E., and Thun, M.J. Cancer Statistics, 2003. CA Cancer J. Clin. 53: 5–26, 2003.PubMedCrossRefGoogle Scholar
  6. 6.
    Chu, K.C., Tarone, R.E., Brawley, O.W. Breast cancer trends of black women compared with white women. Archives of Family Medicine 8:521–528, 1999.PubMedCrossRefGoogle Scholar
  7. 7.
    MacMahon, B., Cole, P., Liu, M., Lowe, C.R., Mirra, A.P., Ravin, I., Har, B., Salber, E.J., Valaoras, V.G. and Yuasa, S. Age at first birth and breast cancer risk. Bull. World Health Organ. 34:209–221, 1970.Google Scholar
  8. 8.
    McGregor, D.H., Land, C.E., Choi, K., Tokuoka, S., Liu, P.I., Wakabayashi, I., Beebe, G.W. Breast cancer incidence among atomic bomb survivors, Hiroshima and Nagasaki 1950-1989. J. Natl. Cancer Inst. 59:799–811, 1977.PubMedGoogle Scholar
  9. 9.
    De Waard, F. and Trichopoulos, D. A unifying concept of the etiology of breast cancer. Int. J. Cancer 41:666–669, 1988.PubMedCrossRefGoogle Scholar
  10. 10.
    Henderson, B.E., Ross, R.K. and Pike, M.C. Hormonal chemoprevention of cancer in women. Science 9:633–638, 1993.CrossRefGoogle Scholar
  11. 11.
    Briand, P., Petersen, O.W., van Dews, B. A new diploid nontumorigenic human breast epithelial cell line isolated and propagated in chemically defined medium. In vitro Cell Dev.Biol. 23:181–188, 1987.PubMedCrossRefGoogle Scholar
  12. 12.
    Rosner, B., Colditz, G.A. and Willett, W.C. Reproductive risk factors in a prospective study of breast cancer: The nurses health study. Am. J. Epidemiol. 139:819–835, 1994.PubMedGoogle Scholar
  13. 13.
    Russo, I.H., and Russo, J. Role of hCG and inhibin in breast cancer. Int. J. Oncol. 4:297–306, 1994.PubMedGoogle Scholar
  14. 14.
    Hu, Y.F., Russo, I.H., Ao, X., and Russo, J. Mammary derived growth inhibitor (MDGI) cloned from human breast epithelial cells is expressed in fully differentiated lobular structures. Int. J. Oncol. 11:5–11, 1997.PubMedGoogle Scholar
  15. 15.
    Hu, Y.F., Silva, I.D.C.G., Russo, I.H. Ao, X. and Russo, J. A novel serpin gene cloned from differentiated human breast epithelial cells is a potential tumor suppressor. Proc. Am. Assoc. Cancer Res., 39: 775, 1998.Google Scholar
  16. 16.
    Mailo, D., Russo, J., Sheriff, F., Hu, YF., Tahin, Q., Mihaila, D., Balogh, G. and Russo, I.H. Genomic signature induced my differentiation in the rat mammary gland. Proc. Am. Assoc. Cancer Res. 43:2002.Google Scholar
  17. 17.
    Russo, J., Reina, D., Frederick, J. and Russo, I.H. Expression of phenotypical changes by human breast epithelial cells treated with carcinogens in vitro. Cancer Res. 48:2837–2857, 1988.PubMedGoogle Scholar
  18. 18.
    Russo, J., Mills, M.J, Moussalli, M.J. and Russo, I.H. Influence of breast development and growth properties in vitro. In vitro Cell Develop. Biol. 25:643–649, 1989.CrossRefGoogle Scholar
  19. 19.
    Russo, J., Gusterson, B.A., Rogers, A.E., Russo, I.H., Wellings, S.R. and Van Zwieten, M.J. Comparative study of human and rat mammary tumorigenesis. Lab. Invest. 62:1–32, 1991.Google Scholar
  20. 20.
    Russo, J., Romero, A.L. and Russo, I.H. Architectural pattern of the normal and cancerous breast under the influence of parity. J. Cancer Epidemiol., Biomarkers & Prevention 3:219–224, 1994.Google Scholar
  21. 21.
    Russo, J., Rivera, R. and Russo, I.H. Influence of age and parity on the development of the human breast. Breast Cancer Res. Treat. 23:211–218, 1992.PubMedCrossRefGoogle Scholar
  22. 22.
    Russo, J. Hu, Y-E, Silva, I.D.C.G., and Russo, I.H. Cancer risk related to mammary gland structure and development. Microsc. Res Tech. 52:204–223, 2001.CrossRefGoogle Scholar
  23. 23.
    Russo J, Tay, L.K. and Russo IH. Differentiation of the mammary gland and susceptibility to carcinogenesis. Breast Cancer Res. Treat. 2:5–73, 1982.PubMedCrossRefGoogle Scholar
  24. 24.
    Hu, YE, Russo, I.H., Zalipsky, U., and Russo, J. Lack of involvement of bcl2 and cyclin Dl in the early phases of human breast epithelial cell transformation by environmental chemical carcinogens. Proc. Am. Assoc. Cancer Res. 37:1005a, 1996.Google Scholar
  25. 25.
    Russo, J. and Russo, I.H. Role of differentiation in the pathogenesis and prevention of breast cancer. Endocrine-Related Cancer 4:1–15, 1997.CrossRefGoogle Scholar
  26. 26.
    Russo, J., Hu, Y-E, Yang, X. and Russo, I.H. Developmental, cellular, and molecular basis of human breast cancer: J. Natl. Cancer Inst. Monograph 27, pp 17–38, 2000.CrossRefGoogle Scholar
  27. 27.
    Russo, J. and Russo, I.H. Development of the Human Breast. In: Encyclopedia of Reproduction, (E. Knobil and J.D. Neill, Eds.) Academic Press, New York, Vol. 3, 71–80, 1998.Google Scholar
  28. 28.
    Russo, J. and Russo, I.H. The cellular basis of breast cancer susceptibility. Oncol. Res., 11:169–178, 1999.PubMedGoogle Scholar
  29. 29.
    Russo, J. and Russo, I.H. Development pattern of human breast and susceptibility to carcinogenesis. European J. Cancer Prevent. 2:85–100, 1993.Google Scholar
  30. 30.
    Russo, J. and Russo, I.H. Toward a physiological approach to breast cancer prevention. Cancer Epidemiology, Biomarkers & Prev. 3:353–364, 1994.Google Scholar
  31. 31.
    Xie, J., Haslam, S.Z. Extracellular matrix regulates ovarian hormone-dependent proliferation of mouse mammary epithelial cells. Endocrinology. 138:2466–73, 1997PubMedCrossRefGoogle Scholar
  32. 32.
    Petersen, O.W., Ronnov-Jessen, L., Weaver, V.M., Bissell, M.J. Differentiation and cancer in the mammary gland: shedding light on an old dichotomy. Adv. Cancer Res. 75:135–61, 1998.PubMedCrossRefGoogle Scholar
  33. 33.
    Russo, J., Lynch, H., and Russo, I.H. Mammary gland architecture as a determining factor in the susceptibility of the human breast to cancer. Breast Journal 7:278–291, 2001.PubMedCrossRefGoogle Scholar
  34. 34.
    Kumar, V., Stack, G.S., Berry, M., Jin, J.R. and Chambon, P. Functional domains of the human estrogen receptor. Cell 51:941–951, 1987.PubMedCrossRefGoogle Scholar
  35. 35.
    King, R.J.B. Effects of steroid hormones and related compounds on gene transcription. Clin. Endocrinol. 36:1–14, 1992.CrossRefGoogle Scholar
  36. 36.
    Soto, A.M. and Sonnenschein, C. Cell proliferation of estrogen-sensitive cells: the case for negative control. Endocr. Rev. 48:52–58, 1987.Google Scholar
  37. 37.
    Huseby, R.A., Maloney, T.M. and McGrath, CM. Evidence for a direct growth-stimulating effect of estradiol on human MCF-7 cells in vitro. Cancer Res. 144:2654–2659, 1987.Google Scholar
  38. 38.
    Huff, K.K., Knabbe, C., Lindsey, R., Kaufman, D., Bronzert, D., Lippman, M.E., Dickson, R.B. Multi hormonal regulation of insulin-like growth factor-1-related protein in MCF-7 human breast cancer cells. Mol. Endocrinol. 2:200–208, 1988.PubMedCrossRefGoogle Scholar
  39. 39.
    Dickson, R.B., Huff, K.K., Spencer, E.M. and Lippman, M.E. Introduction of epidermal growth factor related polypeptides by 17β-estradiol in MCF-7 human breast cancer cells. Endocrinol. 118:138–142, 1986.CrossRefGoogle Scholar
  40. 40.
    Page, M.J., Field, J.K., Everett, P and Green, CD. Serum regulation of the estrogen responsiveness of the human breast cancer cell line MCF-7. Cancer Res. 43:1244–1250, 1983.PubMedGoogle Scholar
  41. 41.
    Katzenellenbogen, B.S., Kendra, K.L., Norman, M.J. and Berthois, Y. Proliferation, hormonal responsiveness and estrogen receptor content of MCF-7 human breast cancer cells growth in the short-term and long-term absence of estrogens. Cancer Res. 47:4355–4360, 1987.PubMedGoogle Scholar
  42. 42.
    Aakvaag, A., Utaacker, E., Thorsen, T., Lea, O.A. and Lahooti, H. Growth control of human mammary cancer cells MCF-7 cells in culture: Effect of estradiol and growth factors in serum containing medium. Cancer Res. 50:7806–810, 1991.Google Scholar
  43. 43.
    Dell’aquilla, M.L., Pigott, D.A., Bonaquist, D.L. and Gaffney, E.V. A factor from plasma derived human serum that inhibits the growth of the mammary cell line MCF-7: characterization and purification. J. Natl. Cancer Inst. 72:291–298, 1984.Google Scholar
  44. 44.
    Markaverich, B.M., Gregory, R.R., Alejandro, M.A., Clark, J.H., Johnson, G.A. and Middleditch, B.S. Methyl p-hydroxphenyllactate. An inhibitor of cell growth and proliferation and an endogenous ligand for nuclear type-11 binding sites. J. Biol. Chem. 263:7203–7210, 1988.PubMedGoogle Scholar
  45. 45.
    Russo, J., Ao, X., Grill, C and Russo, I.H. Pattern of distribution of cells positive for estrogen receptor a and progesterone receptor in relation to proliferating cells in the mammary gland. Breast Cancer Res. Treat. 53:217–227, 1999.PubMedCrossRefGoogle Scholar
  46. 46.
    Bonte, F. Constitution de la matrice extracellulaire normal et pathologique. Arch. Anat. Cytol. Path. 433:170–172, 1995.Google Scholar
  47. 47.
    Shrevestha, P., Kusakabe, M., Mori, M. Tenascin in human neoplasia: Immuno-histochemical observations using seven different clones of monoclonal antibodies. Int. J. Oncol. 8:741–755, 1996.Google Scholar
  48. 48.
    Chiquet-Ehrisman, R., Mackie, E.J., Pearson, C.A., Sakakura, T. Tenascin: An extracellular matrix protein involved in tissue interactions during fetal development and oncogenesis. Cell 47:131–139, 1986.CrossRefGoogle Scholar
  49. 49.
    Wrenn, D.S., Griffin,G.L., Senior, R.M., Mechan, R.P. Characterization of biologically active domain on elastin: Identification of monoclonal antibody to a cell recognition site. Biochemistry 25:5172–5176, 1986.PubMedCrossRefGoogle Scholar
  50. 50.
    Hall, A. Rho GT Pases and the actin cytoskeleton. Science 279:509–514, 1998.PubMedCrossRefGoogle Scholar
  51. 51.
    Foster, R., Hu, K.Q., Lu, Y., Nolan, K.M., Thissen, J., Settleman, J. Identification of a novel human Rho protein with unusual properties: GTPase deficiency and in vivo farnesylation. Mol. Cell Biol. 6:2689–2699, 1996.Google Scholar
  52. 52.
    Guasch, R.M., Scambler, P., Jones, G.E., Ridley, A.J. RhoE regulates actin cytoskeleton organization and cell migration. Mol. Cell. Biol. 18:4761–4771, 1998.PubMedGoogle Scholar
  53. 53.
    Peng, Y, Du, K., Ramirez, S., Diamond, R.H., Taub, R. Mitogenic up-regulation of the PRL-1 protein-tyrosine phosphatase gene by Egr-1. Egr-1 activation is an early event in liver regeneration. J. Biol. Chem. 274:4513–4520, 1999.PubMedCrossRefGoogle Scholar
  54. 54.
    Takano, S., Fukuyama, H., Fukumoto, M., Kimura, J., Xue, J.H., Ohashi, H., Fujita, J. PRL-1, a protein tyrosine phosphatase is expressed in neurons and oligodendrocytes in the brain and induced in the cerebral cortex following transient forebrain ischemia. Mol. Brain Res. 40:105–115, 1996.PubMedCrossRefGoogle Scholar
  55. 55.
    Diamond, R.H., Peters, C., Jung, S.P., Greenbaum, L.E., Haber, B.A., Silberg, D.G., Traber, P.G., Taub, R. Expression of PRL-1 nuclear PTPase is associated with proliferation in liver but with differentiation in intestine. Am. J. Physiol. 271:121–129, 1996.Google Scholar
  56. 56.
    Rundle, C.H., Kappen, C. Developmental expression of the murine Prl-1 protein tyrosine phosphatase gene. J. Exp. Zool. 283:612–617, 1999.PubMedCrossRefGoogle Scholar
  57. 57.
    Peng, Y, Genin, A., Spinner, N.B., Diamond, R.H., Taub, R. The gene encoding human nuclear protein tyrosine phosphatase, PRL-1. Cloning, chromosomal localization, and identification of an intron enhancer. J. Biol. Chem. 273: 17286–17295, 1998.PubMedCrossRefGoogle Scholar
  58. 58.
    Phillips, L.S., Pao, C.I., Villafuerte, B.C. Molecular regulation of insulin-like growth factor-1 and its principal binding protein, IGFBP-3. Prog Nucleic Acid Res. Mol. Biol. 60:195–265, 1998.PubMedCrossRefGoogle Scholar
  59. 59.
    Oh, Y IGFBPs and neoplastic models. New concepts for roles of IGFBPs in regulation of cancer cell growth. Endocrine 71:111–113, 1997.CrossRefGoogle Scholar
  60. 60.
    Cubbage, M.L., Suwanichkul, A., Powell, D.R. Insulin-like growth factor binding protein-3. Organization of the human chromosomal gene and demonstration of promoter activity.J Biol. Chem. 265:21:12642–12649, 1990.Google Scholar
  61. 61.
    Coverley JA, Baxter RC. Phosphorylation of insulin-like growth factor binding proteins. Mol Cell Endocrinol 128:1–5, 1997.PubMedCrossRefGoogle Scholar
  62. 62.
    Brotherick, I., Robson, C.N., Bronell, D.A. et al. Cytokeratin expression in breast cancer: phenotypic changes associated with disease progression. Cytometry 32:301–308, 1998.PubMedCrossRefGoogle Scholar
  63. 63.
    Welch, D.R., and Wei, L.L. Genetic and epigenetic regulation of human breast cancer progression and metastasis. Endocrine Related Cancer 5:155–197, 1998.CrossRefGoogle Scholar
  64. 64.
    Aoki, R., Tanaka, S., Haruma, K., Yoshihara, M., Sumii, K., et al. MUC-1 expression as a predictor of the curative endoscopic treatment of submucosally invasive colorectal carcinoma. Dis. Colon Rectum 41:1262–1272, 1998.PubMedCrossRefGoogle Scholar
  65. 65.
    Segal Eiras, A., and Croce, M.V. Breast cancer associated mucin: a review. Allergol. Immunopathol. 25:176–181, 1997.Google Scholar
  66. 66.
    Manni, A., Badger, B., Wei, L. et al. Hormonal regulation of insulin-growth factor II and insulin growth factor binding protein expression by breast cancer cells in vivo. Evidence for epithelial stromal interactions. Cancer Research 54:2934–2942, 1994.Google Scholar
  67. 67.
    Russo, J., Calaf, G. and Russo, I.H. A critical approach to the malignant transformation of human breast epithelial cells. CRC Critical Reviews in Oncogenesis 4:403–417, 1993.Google Scholar
  68. 68.
    Chandra, T., Stackhouse, R., Kidd, V.J., Robson, K.J. and Woo, S.L. Sequence homology between human alpha 1-antichymotrypsin, alpha 1-antitrypsin and antibrombin III. Biochemistry 22:5055–5061, 1983.PubMedCrossRefGoogle Scholar
  69. 69.
    Rubin, H., Wang, Z.M., Nickbarg, E.B., McLarney, S., Naidoo, N., Schoenberger, O.L., Johnson, J.L. and Cooperman, B.S. Cloning expression, purification and biological activity of recombinant native and variant human al-antichymotrypsin. J. Biol. Chem. 265:1199–1207, 1990.PubMedGoogle Scholar
  70. 70.
    Wellings, S.R., Jansen, M.M. and Marcum, R.G. An atlas of sub-gross pathology of the human breast with special reference to possible pre-cancerous lesions. J.N.C.I. 55:231–275, 1975.Google Scholar
  71. 71.
    Huynh, H.T., Larsson, C., Narod, S. and Pollak, M. Tumor suppressor activity of the gene encoding mammary-derive growth inhibitor. Cancer Res. 55:2225–2231, 1995.PubMedGoogle Scholar
  72. 72.
    Lehmann, W, Graetz, H., Schutt, M. and Langen, P. Chalonelike inhibition of Ehrlich ascites cell proliferation in vitro by an ultra-filtrate obtained from the ascetic fluid. Acta Biol. Med. Germ. 36:K43–K52, 1977.Google Scholar
  73. 73.
    Veerkamp, J.H., Peeters, R.A. and Maatman, R.G. Structural and functional features of different types of cytoplasmic fatty acid-binding proteins. Biochim. Biophys. Acta 1081: 1–24, 1991.PubMedCrossRefGoogle Scholar
  74. 74.
    Bohmer, F.D., Kraft, R., Otto, A., Wernstedt, C., Hellman, U., Kurtz, A., Muller, T., Rohde, K., Etzold, G., Lehmann, W, Langen, P., Heldin, C.H. and Grosse, R. Identification of a polypeptide growth inhibitor from bovine mammary gland. Sequence homology to fatty acids and retinoid binding proteins. J. Biol. Chem. 262:15137–15143, 1987.PubMedGoogle Scholar
  75. 75.
    Jones, P.D., Carne, A., Bass, N.M. and Grigor, M.R. Isolation and characterization of fatty acid binding proteins from mammary tissue of lactating rats. Biochem. J. 251:919–925, 1988.PubMedGoogle Scholar
  76. 76.
    Tweedie, S. and Edwards, Y. cDNA sequence for mouse heart fatty acid binding protein, H-FABP. Nucleic Acid Res. 17:4374–4377, 1989.PubMedCrossRefGoogle Scholar
  77. 77.
    Phelan, C.M., Larsson, C., Baird, S., Futreal, P.A., Ruttledge, M.H., Morgan, K., Tonin, P., Hung, H., Korneluk, R.G., Pollak, M.N. and Narod, S.A. The human mammary-derived growth inhibitor (MDGI) gene: genomic structure and mutation analysis in human breast tumors. Genomics 34:63–68, 1996.PubMedCrossRefGoogle Scholar
  78. 78.
    Genuardi, M., TsI.Hira, H., Anderson, D.E. & Saunders, G.F. Distal deletion of chromosome 1p in ductal carcinoma of the breast. Am. J. Hum. Genet. 45:73–82, 1989.PubMedGoogle Scholar
  79. 79.
    Bieche, I., Champeme, M.H. and Lidereau, R. A tumor suppressor gene on chromosome 1p32 pter controls the amplification of myc family genes in breast cancer. Cancer Res. 54:4274–4276, 1994.PubMedGoogle Scholar
  80. 80.
    Bieche, I., Champeme, M.H., Matifas, F., Cropp, C.S., Callahan, R. and Lidereau, R. Two distinct regions involved in lp deletion in human primary breast cancer. Cancer Res. 53:1990–1994, 1993.PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2004

Authors and Affiliations

  • Jose Russo
    • 1
  • Irma H. Russo
    • 1
  1. 1.Breast Cancer Research LaboratoryFox Chase Cancer CenterPhiladelphiaUSA

Personalised recommendations