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


High serum concentrations of estradiol (E2) equivalent tothose observed in the luteal phase of the menstrual cycle stimulate bothepithelial cell proliferation and progesterone receptor (PgR) expression innormal human breast tissue xenografted into athymic nude mice. We reporthere the results of further investigations designed to determine whether theinduction of PgR expression and proliferation require differentE2 concentrations and whether proliferating cells expressedthe PgR. In untreated normal breast xenografts, the PgR was virtuallyundetectable and proliferation was at basal levels. Progesterone (Pg)treatment alone had no effect compared to no treatment. Treatment withE2 at follicular phase serum concentrations maximallyincreased PgR expression but was without effect on proliferation. However,treatment with E2 at luteal phase serum concentrations, aloneor in combination with Pg, significantly increased both the PgR content andthe proliferation of the breast epithelium. These experimentally deriveddata reflected the observations made on normal breast tissue at surgicalbiopsy where PgR content was similar in both halves of the menstrual cycle,whereas proliferation was significantly higher in the luteal phase. Finally,using double labelling techniques, it was demonstrated that proliferatingepithelial cells rarely expressed PgR in normal breast tissue obtained atsurgical biopsy. These results suggest that the threshold ofE2 required to induce PgR expression in normal human breastepithelial cells is lower than that required to induce proliferation andthat the majority of proliferating breast cells do not express the PgR.

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  1. 1.

    Key TJA, Pike MC: The role of oestrogens and progestins in the epidemiology and prevention of breast cancer. Eur J Cancer Clin Oncol 24: 29–43, 1988

    Google Scholar 

  2. 2.

    Clarke CL, Sutherland RL: Progestin regulation of cellular proliferation. Endocrine Rev 11: 266–301, 1990

    Google Scholar 

  3. 3.

    Clarke CL, Sutherland RL: Progestin regulation of cellular proliferation: update 1993. Endocrine Rev 1: 132–135, 1993

    Google Scholar 

  4. 4.

    Ferenczy A, Bertrand G, Gelfand MM: Proliferation kinetics of human endometrium during the normal menstrual cycle. Gynecology 133: 859–867, 1979

    Google Scholar 

  5. 5.

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

    Google Scholar 

  6. 6.

    Meyer JS: Cell proliferation in normal breast ducts, fibroadenomas, and other ductal hyperplasias measured by nuclear labelling with tritiated thymidine: effects of menstrual phase, age, and oral contraceptive hormones. Hum Pathol 8: 67–81, 1977

    Google Scholar 

  7. 7.

    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 

  8. 8.

    Potten CS, Watson RJ, Williams GT, Tickle S, Roberts SA, Harris M, Howell A: The effect of age and menstrual cycle upon proliferative activity of the normal human breast. Br J Cancer 58: 163–170, 1988

    Google Scholar 

  9. 9.

    Thomas DB: Do hormones cause breast cancer? Cancer 53: 595–604, 1984

    Google Scholar 

  10. 10.

    Anderson TJ, Battersby S, King RJB, McPherson K, Going JJ: Oral contraceptive use influences resting breast proliferation. Hum Pathol 20: 1139–1144, 1989

    Google Scholar 

  11. 11.

    King RJB: A discussion of the roles of oestrogen and progestin in human mammary carcinogenesis. J Steroid Biochem Mol Biol 39: 811–818, 1991

    Google Scholar 

  12. 12.

    Gompel A, Malet A, Spritzer P, Lalardrie JP, Kuttenn F, Mauvais-Jarvis P: Progestin effect on cell proliferation and 17β-hydroxysteroid dehydrogenase activity in normal breast cells in culture. J Clin Endocrinol Metab 63: 1174–1180, 1986

    Google Scholar 

  13. 13.

    Malet C, Gompel A, Spritzer P, Bricout N, Yaneva H, Mowszowicz I, Kuttenn F, Mauvais-Jarvis P: Tamoxifen and hydroxytamoxifen isomers versus estradiol effects on normal breast cells in culture. Cancer Res 48: 7193–7199, 1988

    Google Scholar 

  14. 14.

    Richards J, Imagawa W, Balakrishnan A, Edery M, Nandi S: The lack of effect of phenol red or estradiol on the growth response of human, rat and mouse mammary cells in primary culture. Endocrinol 123: 1335–1340, 1988

    Google Scholar 

  15. 15.

    Gabelman BM, Emerman JT: Effects of estrogen, epidermal growth factor, and transforming growth factor-α on the growth of human breast epithelial cells in primary culture. Experiment Cell Res 201: 113–118, 1992

    Google Scholar 

  16. 16.

    Laidlaw IJ, Clarke RB, Howell A, Owen AWMC, Potten CS, Anderson E: The proliferation of normal human breast tissue implanted into athymic nude mice is stimulated by estrogen but not progesterone. Endocrinology 136: 164–171, 1995

    Google Scholar 

  17. 17.

    Katzenellenbogen BS, Norman MJ: Multihormonal regulation of the progesterone receptor in MCF-7 human breast cancer cells: interrelationships among insulin/insulin-like growth factor-I, serum, and estrogen. Endocrinology 126: 891–898, 1990

    Google Scholar 

  18. 18.

    Williams G, Anderson E, Howell A, Watson R, Coyne J, Roberts SA, Potten CS: Oral contraceptive (OCP) use increases proliferation and decreases oestrogen receptor content of epithelial cells in the normal human breast. Int J Cancer 48: 206–210, 1991

    Google Scholar 

  19. 19.

    Battersby S, Robertson BJ, Anderson TJ, King RJB, McPherson K: Influence of menstrual cycle, parity and oral contraceptive use on steroid hormone receptors in normal breast. Br J Cancer 65: 601–607, 1992

    Google Scholar 

  20. 20.

    Soderqvist G, von Schoultz B, Tani E, Skoog L: Estrogen and progesterone receptor content in breast epithelial cells from healthy women during the menstrual cycle. Am J Obstet Gynecol 168: 874–879, 1993

    Google Scholar 

  21. 21.

    Aksel S: Hormonal characteristics of long cycles in fertile women. Fertil Steril 36: 521–523, 1981

    Google Scholar 

  22. 22.

    Fotherby K: Endocrinology of the menstrual cycle and pregnancy. In: Makin HLJ (ed) Biochemistry of Steroid Hormones, 2nd edition. Blackwell Scientific Publications, Oxford, 1984, pp 409–440

    Google Scholar 

  23. 23.

    Vermeulen A, Verdonck L: Sex hormone concentrations in post-menopausal women. Clin Endocrinol (Oxf) 9: 59–66, 1978

    Google Scholar 

  24. 24.

    Lessey BA, Killam AP, Metzger DA, Haney AF, Greene GL, McCarty KS: Immunohistochemical analysis of human uterine oestrogen and progesterone receptors throughout the menstrual cycle. J Clin Endocrinol Metab 67: 334–341, 1988

    Google Scholar 

  25. 25.

    Press MF, Udove JA, Greene GL: Progesterone receptor distribution in the human endometrium: analysis using monoclonal antibodies to the human progesterone receptor. Am J Pathol 131: 112–124, 1988

    Google Scholar 

  26. 26.

    Cassanelli S, Louis J, Seigneurin D: Progesterone receptor heterogeneity in MCF-7 cell subclones is related to clonal origin and kinetics data. Tumor Biol 16: 222–229, 1995

    Google Scholar 

  27. 27.

    Rostagno P, Caldani C, Lahlou B: Cell cycle expression of steroid receptors determined by image analysis on human breast cancer cell line: a hypothesis on the effects of anti-estrogens. Breast Cancer Res Treat 37: 77–87, 1996

    Google Scholar 

  28. 28.

    McManus MJ, Welsch CW: The effect of estrogen, progesterone, thyroxine, and human placental lactogen on DNA synthesis of human breast ductal epithelium maintained in athymic nude mice. Cancer 54: 1920–1927, 1984

    Google Scholar 

  29. 29.

    Pike MC, Urskin G, Spicer DV: Experiments on proliferation of normal human breast tissue in nude mice do not show that progesterone does not stimulate breast cells. Endocrinology 137: 1, 1996

    Google Scholar 

  30. 30.

    Jeng M-H, Parker CJ, Jordan VC: Estrogenic potential in oral contraceptives to stimulate human breast cancer cell proliferation. Cancer Res 52: 6539–6546, 1992

    Google Scholar 

  31. 31.

    Catherino WH, Jeng M-H, Jordan VC: Norgestrel and gestodone stimulate breast cancer cell growth through an oestrogen receptor mediated mechanism. Br J Cancer 67: 945–952, 1993

    Google Scholar 

  32. 32.

    Chang K-J, Lee TT, Linares-Cruz G, Fournier S, deLignieres B: Influences of percutaneous administration of estradiol and progesterone on human breast epithelial cell cycle in vivo. Fertil Steril 63: 785–791, 1995

    Google Scholar 

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Correspondence to Robert B. Clarke.

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Clarke, R.B., 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, 121–133 (1997).

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  • estrogen
  • normal breast
  • progesterone
  • progesterone receptor
  • proliferation