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Pattern of distribution of cells positive for estrogen receptor α and progesterone receptor in relation to proliferating cells in the mammary gland

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Abstract

Since cell proliferation is indispensable for the growth and development of the breast, and estrogens are considered to play a major role in promoting cell proliferation, while progesterone influences its differentiation, the present work was designed with the purpose of verifying the relationship between cells containing steroid hormone receptors and proliferating cells in the normal human breast. Twelve breast samples were analyzed for their content of lobules type 1 (Lob1), Lob2, Lob3, and Lob4, and the number of cells containing estrogen receptor alpha (ER-α), progesterone receptor (PgR), or expressing Ki67 antibody was determined by double immunocytochemical technique with specific antibodies. The highest percentage of ER-α, PgR, and Ki67 positive cells was found in Lob1, with a progressive reduction in the more differentiated Lob2 and Lob3. ER-α and PgR positive cells were found exclusively in the breast epithelium and were negative for Ki67, while cells positive for Ki67 did not express receptors. These findings were compared with the distribution of ER-α and PgR in the autoradiographs of mammary gland of young virgin rats inoculated with 3H-thymidine for determination of the DNA labeling index (DNA-LI). Both the DNA-LI and the percentage of ER-α and PgR positive cells were maximal in the epithelium of terminal end buds, and these values were reduced in alveolar buds and lobules. ER-α and PgR positive cells did not proliferate, and those cells that had incorporated 3H-thymidine were negative for both receptors. Our results led us to conclude that the content of ER-α and PgR in the normal mammary tissue varies with the degree of lobular development, in parallel with cell proliferation. However, the expression of receptors occurs in cells other than the proliferating cells, indicating that they represent at least two separate cell populations. These findings open new avenues towards the understanding of the mechanisms through which estrogens and progesterone affect the proliferative activity of breast epithelial cells, and their role in the initiation of the cascade of events that leads a normal cell to cancer.

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References

  1. Russo J, Russo IH:Role of hormones in human breast development: The menopausal breast. In: Progress in the Management of Menopause. Parthenon Publishing, London, 1997, pp 184–193

    Google Scholar 

  2. Russo IH, Russo J: Role of hormones in cancer initiation and progression. J Mammary Gland Biol Neoplasia 3: 49–61, 1998

    Google Scholar 

  3. Russo J, Russo IH: Role of differentiation in the pathogenesis and prevention of breast cancer. Endocrine Related Cancer 4: 7–21, 1997

    Google Scholar 

  4. Calaf G, Alvarado ME, Bonney GE, Amfoh KK, Russo J: Influence of lobular development on breast epithelial cell proliferation and steroid hormone receptor content. Int J Oncol 7: 1285–1288, 1995

    Google Scholar 

  5. Lippman ME, Dickson RB, Gelmann EP, Rosen N, Knabbe C, Bates S, Bronzert D, Huff K, Kasid A: Growth regulation of human breast carcinoma occurs through regulated growth factor secretion. J Cell Biochem 35: 1–16, 1987

    Google Scholar 

  6. Meyer JS: Cell proliferation in normal human breast ducts, fibroadenomas, and other duct hyperplasias, measured by nuclear labeling with tritiated thymidine. Hum Path 8: 67–81, 1977

    Google Scholar 

  7. Masters JRW, Drife JO, Scarisbrick JJ: Cyclic variations of DNA synthesis in human breast epithelium. J Natl Cancer Inst 58: 1263–1265, 1977

    Google Scholar 

  8. Ferguson DJP, Anderson TJ: Morphologic evaluation of cell turnover in relation to the menstrual cycle in the ‘resting’ human breast. Br J Cancer 44: 177–181, 1981

    Google Scholar 

  9. Anderson TJ, Ferguson DJP, Raab GM: Cell turnover in the ‘resting’ human breast: influence of parity, contraceptive pill, age and laterality. Br J Cancer 46: 376–382, 1982

    Google Scholar 

  10. Russo J, Russo IH: Estrogens and cell proliferation in the human breast. J Cardiovasc Pharmacol 28: 19–23, 1996

    Google Scholar 

  11. Kumar V, Stack GS, Berry M, Jin JR, Chambon P: Functional domains of the human estrogen receptor. Cell 51: 941–951, 1987

    Google Scholar 

  12. King RJB: Effects of steroid hormones and related compounds on gene transcription. Clin Endocrinol 36: 1–14, 1992

    Google Scholar 

  13. Soto AM, Sonnenschein C: Cell proliferation of estrogensensitive cells: the case for negative control. Endocr Rev 48: 52–58, 1987

    Google Scholar 

  14. Huseby RA, Maloney TM, 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 

  15. Huff KK, Knabbe C, Lindsey R, Kaufman D, Bronzert D, Lippman ME, Dickson RB: Multihormonal regulation of insulin-like growth factor-1-related protein in MCF-7 human breast cancer cells. Mol Endocrinol 2: 200–208, 1988

    Google Scholar 

  16. Dickson RB, Huff KK, Spencer EM, Lippman ME: Introduction of epidermal growth factor related polypeptides by 17b-estradiol in MCF-7 human breast cancer cells. Endocrinol 118: 138–142, 1986

    Google Scholar 

  17. Katzenellenbogen BS, Kendra KL, Norman MJ, Berthois Y: Proliferation, hormonal responsiveness and estrogen receptor content of MCF-7 human breast cancer cell growth in the short-term and long-term absence of estrogens. Cancer Res 47: 4355–4360, 1987

    Google Scholar 

  18. Petersen OW, Hoyer PE, van Deurs B: Frequency and distribution of estrogen receptor positive cells in normal, nonlactating human breast tissue. Cancer Res 47: 5748–5751, 1987

    Google Scholar 

  19. Jacquemier JD, Hassouin J, Torente M, Martin PM: Distribution of estrogen and progesterone receptors in healthy tissue adjacent to breast lesions at various stages: immunohistochemical study of 107 cases. Breast Cancer Res Treat 15: 109–117, 1990

    Google Scholar 

  20. McGuire W, Carbone P, Vollmer R (eds): Estrogen Receptors in Human Breast Cancer. Raven Press, New York, 1975

    Google Scholar 

  21. Dickson R, Lippman M: Control of human breast cancer by estrogen, growth factors and oncogenes. In: Lipman ME, Dickson RB (eds) Estrogen Receptors in Human Breast Cancer. Raven Press, New York, 1975

    Google Scholar 

  22. Wittliff JL: Steroid-hormone receptors in breast cancer. Cancer 53: 630–643, 1984

    Google Scholar 

  23. Watts CKW, Handel ML, King RJB, Sutherland RL: Oestrogen receptor gene structure and function in breast cancer. J Steroid Biochem Molec Biol 41: 5293–5536, 1992

    Google Scholar 

  24. Aakvaag A, Utaacker E, Thorsen T, Lea OA, 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: 7806–7810, 1990

    Google Scholar 

  25. Dell'aquilla ML, Pigott DA, Bonaquist DL, Gaffney EV: 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 

  26. Kuiper GGJM, Enmark E, Pelto-Huikko M, Nilsson S, Gustaffson J-°A: Cloning of a novel estrogen receptor expressed in rat prostate and ovary. Proc Natl Acad Sci USA 93: 5925–5930, 1996

    Google Scholar 

  27. Byers M, Kuiper GGJM, Gustaffson J-°A, Park-Sarge OK: Estrogen receptor-b mRNA expression in rat ovary: downregulation by gonadotropins. Mol Endocrinol 11: 172–182, 1997

    Google Scholar 

  28. Vladusic EA, Hornby AE, Guerra-Vladusic FK, Lupu R: Expression of estrogen receptor b messenger RNA variant in human breast cancer. Cancer Res 58: 210–214, 1998

    Google Scholar 

  29. Longacre TA, Bartow SA: A correlative morphologic study of human breast and endometrium in the menstrual cycle. Am J Surg Pathol 10: 382–393, 1986

    Google Scholar 

  30. Going JJ, Anderson TJ, Battersby S: Proliferative and secretory activity in human breast during natural and artificial menstrual cycles. Am J Pathol 130: 193–204, 1988

    Google Scholar 

  31. Potten CS, Watson RJ, Williams GT: The effect of age and menstrual cycle upon proliferative activity of the normal human breast. Br J Cancer 58: 163–170, 1988

    Google Scholar 

  32. Clark RB, Howell A, Potter CS, Anderson E: Dissociation between steroid receptor expression and cell proliferation in the human breast. Cancer Res 57: 4987–4991, 1997

    Google Scholar 

  33. Laidlaw IJ, Clark RB, Howell A, Owen AWMC, Potten CS, Anderson E: Estrogen and progesterone stimulate proliferation of normal human breast tissue implanted in athymic nude mice. Endocrinol 136: 164–171, 1995

    Google Scholar 

  34. Clarke RB, Howell A, Anderson E: Estrogen sensitivity of normal human breast tissue in vivo and implanted into athymic nude mice; analysis of the relationship between estrogen-induced proliferation and progesterone receptor expression. Breast Cancer Res Treat 45: 121–183, 1997

    Google Scholar 

  35. Goodman HM: Basic Medical Endocrinology. Raven Press, New York, 1994, pp 288–290

    Google Scholar 

  36. Russo J, Russo IH: Influence of differentiation and cell kinetics on the susceptibility of the rat mammary gland to carcinogenesis. Cancer Res 40: 2677–2687, 1980

    Google Scholar 

  37. Russo J, Rivera R, Russo IH: Influence of age and parity on the development of the human breast. Breast Cancer Res Treat 23: 211–218, 1992

    Google Scholar 

  38. Russo J, Russo IH: Biology of disease. Biological and molecular bases of mammary carcinogenesis. Lab Invest 57: 112–137, 1987

    Google Scholar 

  39. Key G, Becker MH, Baron B, Duchrow M, Schluter C, Flad HD, Gerdes J: New Ki-67-equivalent murine monoclonal antibodies (MIB1–3) generated against bacterially expressed parts of the Ki-67 cDNA containing three 62 base pair repetitive elements encoding for the Ki-67 epitope. Lab Invest 68: 629–636, 1993

    Google Scholar 

  40. Haslam S: Role of sex steroid hormones in normal mammary gland function. In: Neville MC, Daniel CW (eds) The Mammary Gland: Development, Regulation and Function. Plenum Press, New York, 1987, pp 499–533

    Google Scholar 

  41. Clarke R, Dickson RB, Lippman ME: Hormonal aspects of breast cancer. Growth factors, drugs and stromal interactions. Crit Rev Oncol Hematol 12: 1–23, 1992

    Google Scholar 

  42. Knabbe C, Lippman ME, Wakefield LM, et al.: Evidence that transforming growth factor b is a hormonally regulated negative growth factor in human breast cancer cells. Cell 48: 417–428, 1987

    Google Scholar 

  43. Russo J, Reina D, Frederick J, Russo IH: Expression of phenotypical changes by human breast epithelial cells treated with carcinogens in vitro. Cancer Res 48: 2837–2857, 1998

    Google Scholar 

  44. Russo J, Calaf G, Russo IH: A critical approach to the malignant transformation of human breast epithelial cells. Crit Rev Oncogen 4: 403–417, 1993

    Google Scholar 

  45. Russo J, Gusterson BA, Rogers A, Russo IH, Wellings SR, van Zwieten MJ: Biology of breast disease. Comparative study of human and rat mammary tumorigenesis. Lab Invest 62: 244–278, 1990

    Google Scholar 

  46. Habel LA, Stamford JL: Hormone receptors and breast cancer. Epidemiol Rev 15: 209–219, 1993

    Google Scholar 

  47. Harlan LC, Coates RJ, Block G: Estrogen receptor status and dieting intakes in breast cancer patients. Epidemiology 4: 25–31, 1993

    Google Scholar 

  48. Moolgavkar SH, Day NE, Stevens RG: Two-stage model for carcinogenesis: epidemiology of breast cancer in females. J Natl Cancer Inst 65: 559–569, 1980

    Google Scholar 

  49. Kodama F, Green GL, Salmon SE: Relation of estrogen receptor expression to clonal growth and antiestrogen effects on human breast cancer cells. Cancer Res 45: 2720–2724, 1985

    Google Scholar 

  50. Podhajcer OL, Bravo AL, Sorin I, Guman N, Cerdeiro R, Mordoh J: Determination of DNA synthesis, estrogen Hormone receptors and breast cell proliferation 227 receptors, and carcinoembryonic antigen in isolated cellular subpopulations of human breast cancer. Cancer 58: 720–729, 1986

    Google Scholar 

  51. Hu, YF, Lau KM, Ho SM, Russo J: Increased expression of estrogen receptor b in chemically transformed human breast epithelial cells. Int J Oncol 12: 1225–1228, 1998

    Google Scholar 

  52. Foster JS, Wimalasena J: Estrogen regulates activity of cyclin-dependent kinases and retinoblastoma protein phosphorylation in breast cancer cells. Mol. Endocrinol 10: 488–498, 1996

    Google Scholar 

  53. Wang W, Smith R, Burghardt R, Safe SH: 17b estradiolmediated growth inhibition of MDA-MB 468 cells stably transfected with the estrogen receptor: cell cycle effects. Mol. Cell Endocrinol 133: 49–62, 1997

    Google Scholar 

  54. Levenson AS, Jordan VC: Transfection of human estrogen receptor (ER)cDNAintoERnegative mammalian cell lines. J Steroid Biochem Mol Biol 51: 229–239, 1994

    Google Scholar 

  55. Weisz A, Bresciani F: Estrogen regulation of protooncogenes coding for nuclear proteins. Crit Rev Oncogen 4: 361–388, 1993

    Google Scholar 

  56. Zajchowski DA, Sager R, Webster L: Estrogen inhibits the growth of estrogen receptor negative, but not estrogen receptor positive, human mammary epithelial cells expressing a recombinant estrogen receptor. Cancer Res 53: 5004–5011, 1993

    Google Scholar 

  57. Pilat MJ, Christman JK, Brooks SC: Characterization of the estrogen receptor transfected MCF-10A breast cell line 139B6. Breast Cancer Res Treat 37: 253–266, 1996

    Google Scholar 

  58. Calaf G, Tahin Q, Alvarado ME, Estrada S, Cox T, Russo J: Hormone receptors and cathepsin D levels in human breast epithelial cells transformed by chemical carcinogens. Breast Cancer Res Treat 29: 169–177, 1993

    Google Scholar 

  59. Aronica SM, Kraus WL, Katzenellenbogen BS: Estrogen action via the cAMP signaling pathway. Stimulation of adenylate cyclase and cAMP regulated gene transcription. Proc Natl Acad Sci USA 91: 8517–8521, 1994

    Google Scholar 

  60. Pappos TC, Gametahu B, Watson CS: Membrane estrogen receptors identified by multiple antibody labeling and impeded-ligand binding. FASEB J 9: 404–410, 1994

    Google Scholar 

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  1. Breast Cancer Research Laboratory, Fox Chase Cancer Center, Philadelphia, PA

    J. Russo, X. Ao, C. Grill & I.H. Russo

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  1. J. Russo
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Russo, J., Ao, X., Grill, C. et al. Pattern of distribution of cells positive for estrogen receptor α and progesterone receptor in relation to proliferating cells in the mammary gland. Breast Cancer Res Treat 53, 217–227 (1999). https://doi.org/10.1023/A:1006186719322

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