Skip to main content
PMC home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1993 May;67(5):945–952. doi: 10.1038/bjc.1993.175

Norgestrel and gestodene stimulate breast cancer cell growth through an oestrogen receptor mediated mechanism.

W H Catherino 1, M H Jeng 1, V C Jordan 1
PMCID: PMC1968434  PMID: 8494728

Abstract

There is great concern over the long-term influence of oral contraceptives on the development of breast cancer in women. Oestrogens are known to stimulate the growth of human breast cancer cells, and this laboratory has previously reported (Jeng & Jordan, 1991) that the 19-norprogestin norethindrone could stimulate the proliferation of MCF-7 human breast cancer cells. We studied the influence of the 19-norprogestins norgestrel and gestodene compared to a 'non' 19-norprogestin medroxyprogesterone acetate (MPA) on MCF-7 cell proliferation. The 19-norprogestins stimulated proliferation at a concentration of 10(-8) M, while MPA could not stimulate proliferation at concentrations as great as 3 x 10(-6) M. The stimulatory activity of the 19-norprogestins could be blocked by the antioestrogen ICI 164,384, but not by the antiprogestin RU486. Transfection studies with the reporter plasmids containing an oestrogen response element or progesterone response element (vitERE-CAT, pS2ERE-CAT, and PRE15-CAT) were performed to determine the intracellular action of norgestrel and gestodene. The 19-norprogestins stimulated the vitERE-CAT activity maximally at 10(-6) M, and this stimulation was inhibited by the addition of ICI 164,384. MPA did not stimulate vitERE-CAT activity. A single base pair alteration in the palindromic sequence of vitERE (resulting in the pS2ERE) led to a dramatic decrease in CAT expression by the 19-norprogestins, suggesting that the progestin activity required specific response element base sequencing. PRE15-CAT activity was stimulated by norgestrel, gestodene and MPA at concentrations well below growth stimulatory activity. This stimulation could be blocked by RU486. These studies suggest that the 19-norprogestins norgestrel and gestodene stimulate MCF-7 breast cancer cell growth by activating the oestrogen receptor.

Full text

PDF
948

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abrams J. S., Parnes H., Aisner J. Current status of high-dose progestins in breast cancer. Semin Oncol. 1990 Dec;17(6 Suppl 9):68–72. [PubMed] [Google Scholar]
  2. Alexander I. E., Shine J., Sutherland R. L. Progestin regulation of estrogen receptor messenger RNA in human breast cancer cells. Mol Endocrinol. 1990 Jun;4(6):821–828. doi: 10.1210/mend-4-6-821. [DOI] [PubMed] [Google Scholar]
  3. Anderson T. J., Battersby S., King R. J., McPherson K., Going J. J. Oral contraceptive use influences resting breast proliferation. Hum Pathol. 1989 Dec;20(12):1139–1144. doi: 10.1016/s0046-8177(89)80003-6. [DOI] [PubMed] [Google Scholar]
  4. Bergkvist L., Adami H. O., Persson I., Hoover R., Schairer C. The risk of breast cancer after estrogen and estrogen-progestin replacement. N Engl J Med. 1989 Aug 3;321(5):293–297. doi: 10.1056/NEJM198908033210505. [DOI] [PubMed] [Google Scholar]
  5. Braunsberg H. A., Coldham N. G., Wong W. Hormonal therapies for breast cancer: can progestogens stimulate growth? Cancer Lett. 1986 Feb;30(2):213–218. doi: 10.1016/0304-3835(86)90091-1. [DOI] [PubMed] [Google Scholar]
  6. Buehring G. C. Oral contraceptives and breast cancer: what has 20 years of research shown? Biomed Pharmacother. 1988;42(8):525–530. [PubMed] [Google Scholar]
  7. Casagrande J. T., Louie E. W., Pike M. C., Roy S., Ross R. K., Henderson B. E. "Incessant ovulation" and ovarian cancer. Lancet. 1979 Jul 28;2(8135):170–173. doi: 10.1016/s0140-6736(79)91435-1. [DOI] [PubMed] [Google Scholar]
  8. Colletta A. A., Wakefield L. M., Howell F. V., Danielpour D., Baum M., Sporn M. B. The growth inhibition of human breast cancer cells by a novel synthetic progestin involves the induction of transforming growth factor beta. J Clin Invest. 1991 Jan;87(1):277–283. doi: 10.1172/JCI114983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Cormier E. M., Jordan V. C. Contrasting ability of antiestrogens to inhibit MCF-7 growth stimulated by estradiol or epidermal growth factor. Eur J Cancer Clin Oncol. 1989 Jan;25(1):57–63. doi: 10.1016/0277-5379(89)90051-5. [DOI] [PubMed] [Google Scholar]
  10. Croxatto H. B., Díaz S., Pavez M., Brandeis A. Estradiol plasma levels during long-term treatment with Norplant subdermal implants. Contraception. 1988 Oct;38(4):465–475. doi: 10.1016/0010-7824(88)90087-x. [DOI] [PubMed] [Google Scholar]
  11. Dauvois S., Simard J., Dumont M., Haagensen D. E., Labrie F. Opposite effects of estrogen and the progestin R5020 on cell proliferation and GCDFP-15 expression in ZR-75-1 human breast cancer cells. Mol Cell Endocrinol. 1990 Oct 22;73(2-3):171–178. doi: 10.1016/0303-7207(90)90130-z. [DOI] [PubMed] [Google Scholar]
  12. Drill V. A. History of the first oral contraceptive. J Toxicol Environ Health. 1977 Sep;3(1-2):133–138. doi: 10.1080/15287397709529554. [DOI] [PubMed] [Google Scholar]
  13. Goldzieher J. W. Pharmacology of contraceptive steroids: a brief review. Am J Obstet Gynecol. 1989 May;160(5 Pt 2):1260–1264. doi: 10.1016/s0002-9378(89)80010-9. [DOI] [PubMed] [Google Scholar]
  14. Haslam S. Z. Progesterone effects on deoxyribonucleic acid synthesis in normal mouse mammary glands. Endocrinology. 1988 Feb;122(2):464–470. doi: 10.1210/endo-122-2-464. [DOI] [PubMed] [Google Scholar]
  15. Henderson B. E., Ross R. K., Lobo R. A., Pike M. C., Mack T. M. Re-evaluating the role of progestogen therapy after the menopause. Fertil Steril. 1988 May;49(5 Suppl 2):9S–15S. [PubMed] [Google Scholar]
  16. Hulka B. S., Chambless L. E., Kaufman D. G., Fowler W. C., Jr, Greenberg B. G. Protection against endometrial carcinoma by combination-product oral contraceptives. JAMA. 1982 Jan 22;247(4):475–477. [PubMed] [Google Scholar]
  17. Iqbal M. J., Colletta A. A., Houmayoun-Valyani S. D., Baum M. Differences in oestrogen receptors in malignant and normal breast tissue as identified by the binding of a new synthetic progestogen. Br J Cancer. 1986 Sep;54(3):447–452. doi: 10.1038/bjc.1986.196. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Jeng M. H., Jordan V. C. Growth stimulation and differential regulation of transforming growth factor-beta 1 (TGF beta 1), TGF beta 2, and TGF beta 3 messenger RNA levels by norethindrone in MCF-7 human breast cancer cells. Mol Endocrinol. 1991 Aug;5(8):1120–1128. doi: 10.1210/mend-5-8-1120. [DOI] [PubMed] [Google Scholar]
  19. Kaufman D. W., Shapiro S., Slone D., Rosenberg L., Miettinen O. S., Stolley P. D., Knapp R. C., Leavitt T., Jr, Watring W. G., Rosenshein N. B. Decreased risk of endometrial cancer among oral-contraceptive users. N Engl J Med. 1980 Oct 30;303(18):1045–1047. doi: 10.1056/NEJM198010303031807. [DOI] [PubMed] [Google Scholar]
  20. Kay C. R., Hannaford P. C. Breast cancer and the pill--a further report from the Royal College of General Practitioners' oral contraception study. Br J Cancer. 1988 Nov;58(5):675–680. doi: 10.1038/bjc.1988.285. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Klock G., Strähle U., Schütz G. Oestrogen and glucocorticoid responsive elements are closely related but distinct. Nature. 1987 Oct 22;329(6141):734–736. doi: 10.1038/329734a0. [DOI] [PubMed] [Google Scholar]
  22. Labarca C., Paigen K. A simple, rapid, and sensitive DNA assay procedure. Anal Biochem. 1980 Mar 1;102(2):344–352. doi: 10.1016/0003-2697(80)90165-7. [DOI] [PubMed] [Google Scholar]
  23. Liang A. P., Levenson A. G., Layde P. M., Shelton J. D., Hatcher R. A., Potts M., Michelson M. J. Risk of breast, uterine corpus, and ovarian cancer in women receiving medroxyprogesterone injections. JAMA. 1983 Jun 3;249(21):2909–2912. [PubMed] [Google Scholar]
  24. Longman S. M., Buehring G. C. Oral contraceptives and breast cancer. In vitro effect of contraceptive steroids on human mammary cell growth. Cancer. 1987 Jan 15;59(2):281–287. doi: 10.1002/1097-0142(19870115)59:2<281::aid-cncr2820590218>3.0.co;2-a. [DOI] [PubMed] [Google Scholar]
  25. Løber J., Rose C., Salimtschik M., Mouridsen H. T. Treatment of advanced breast cancer with progestins. Acta Obstet Gynecol Scand Suppl. 1981;101:39–46. doi: 10.3109/00016348109157810. [DOI] [PubMed] [Google Scholar]
  26. MacGregor G. R., Caskey C. T. Construction of plasmids that express E. coli beta-galactosidase in mammalian cells. Nucleic Acids Res. 1989 Mar 25;17(6):2365–2365. doi: 10.1093/nar/17.6.2365. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Markiewicz L., Hochberg R. B., Gurpide E. Intrinsic estrogenicity of some progestagenic drugs. J Steroid Biochem Mol Biol. 1992 Jan;41(1):53–58. doi: 10.1016/0960-0760(92)90224-7. [DOI] [PubMed] [Google Scholar]
  28. McGowan L., Parent L., Lednar W., Norris H. J. The woman at risk for developing ovarian cancer. Gynecol Oncol. 1979 Jun;7(3):325–344. doi: 10.1016/0090-8258(79)90111-2. [DOI] [PubMed] [Google Scholar]
  29. McPherson K., Neil A., Vessey M. P., Doll R. Oral contraceptives and breast cancer. Lancet. 1983 Dec 17;2(8364):1414–1415. doi: 10.1016/s0140-6736(83)90936-4. [DOI] [PubMed] [Google Scholar]
  30. McPherson K., Vessey M. P., Neil A., Doll R., Jones L., Roberts M. Early oral contraceptive use and breast cancer: results of another case-control study. Br J Cancer. 1987 Nov;56(5):653–660. doi: 10.1038/bjc.1987.261. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Meirik O., Lund E., Adami H. O., Bergström R., Christoffersen T., Bergsjö P. Oral contraceptive use and breast cancer in young women. A joint national case-control study in Sweden and Norway. Lancet. 1986 Sep 20;2(8508):650–654. doi: 10.1016/s0140-6736(86)90166-2. [DOI] [PubMed] [Google Scholar]
  32. Newhouse M. L., Pearson R. M., Fullerton J. M., Boesen E. A., Shannon H. S. A case control study of carcinoma of the ovary. Br J Prev Soc Med. 1977 Sep;31(3):148–153. doi: 10.1136/jech.31.3.148. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Olsson H., Möller T. R., Ranstam J. Early oral contraceptive use and breast cancer among premenopausal women: final report from a study in southern Sweden. J Natl Cancer Inst. 1989 Jul 5;81(13):1000–1004. doi: 10.1093/jnci/81.13.1000. [DOI] [PubMed] [Google Scholar]
  34. Olsson H., Olsson M. L., Möller T. R., Ranstam J., Holm P. Oral contraceptive use and breast cancer in young women in Sweden. Lancet. 1985 Mar 30;1(8431):748–749. doi: 10.1016/s0140-6736(85)91280-2. [DOI] [PubMed] [Google Scholar]
  35. Oral-contraceptive use and the risk of breast cancer. The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development. N Engl J Med. 1986 Aug 14;315(7):405–411. doi: 10.1056/NEJM198608143150701. [DOI] [PubMed] [Google Scholar]
  36. Orme M. L., Back D. J., Breckenridge A. M. Clinical pharmacokinetics of oral contraceptive steroids. Clin Pharmacokinet. 1983 Mar-Apr;8(2):95–136. doi: 10.2165/00003088-198308020-00001. [DOI] [PubMed] [Google Scholar]
  37. Papa V., Hartmann K. K., Rosenthal S. M., Maddux B. A., Siiteri P. K., Goldfine I. D. Progestins induce down-regulation of insulin-like growth factor-I (IGF-I) receptors in human breast cancer cells: potential autocrine role of IGF-II. Mol Endocrinol. 1991 May;5(5):709–717. doi: 10.1210/mend-5-5-709. [DOI] [PubMed] [Google Scholar]
  38. Paul C., Skegg D. C., Spears G. F. Depot medroxyprogesterone (Depo-Provera) and risk of breast cancer. BMJ. 1989 Sep 23;299(6702):759–762. doi: 10.1136/bmj.299.6702.759. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Peto J. Oral contraceptives and breast cancer: is the CASH study really negative? Lancet. 1989 Mar 11;1(8637):552–552. doi: 10.1016/s0140-6736(89)90088-3. [DOI] [PubMed] [Google Scholar]
  40. Phillips A. The selectivity of a new progestin. Acta Obstet Gynecol Scand Suppl. 1990;152:21–24. doi: 10.3109/00016349009156502. [DOI] [PubMed] [Google Scholar]
  41. Pike M. C., Henderson B. E., Krailo M. D., Duke A., Roy S. Breast cancer in young women and use of oral contraceptives: possible modifying effect of formulation and age at use. Lancet. 1983 Oct 22;2(8356):926–930. doi: 10.1016/s0140-6736(83)90450-6. [DOI] [PubMed] [Google Scholar]
  42. Pollow K., Juchem M., Grill H. J., Elger W., Beier S., Henderson D., Schmidt-Gollwitzer K., Manz B. Gestodene: a novel synthetic progestin--characterization of binding to receptor and serum proteins. Contraception. 1989 Sep;40(3):325–341. doi: 10.1016/0010-7824(89)90096-6. [DOI] [PubMed] [Google Scholar]
  43. Ree A. H., Landmark B. F., Eskild W., Levy F. O., Lahooti H., Jahnsen T., Aakvaag A., Hansson V. Autologous down-regulation of messenger ribonucleic acid and protein levels for estrogen receptors in MCF-7 cells: an inverse correlation to progesterone receptor levels. Endocrinology. 1989 May;124(5):2577–2583. doi: 10.1210/endo-124-5-2577. [DOI] [PubMed] [Google Scholar]
  44. Rosenberg L., Shapiro S., Slone D., Kaufman D. W., Helmrich S. P., Miettinen O. S., Stolley P. D., Rosenshein N. B., Schottenfeld D., Engle R. L., Jr Epithelial ovarian cancer and combination oral contraceptives. JAMA. 1982 Jun 18;247(23):3210–3212. [PubMed] [Google Scholar]
  45. Salmi T. Risk factors in endometrial carcinoma with special reference to the use of estrogens. Acta Obstet Gynecol Scand Suppl. 1979;86:1–119. [PubMed] [Google Scholar]
  46. Schlesselman J. J. Cancer of the breast and reproductive tract in relation to use of oral contraceptives. Contraception. 1989 Jul;40(1):1–38. doi: 10.1016/0010-7824(89)90025-5. [DOI] [PubMed] [Google Scholar]
  47. Shoupe D., Mishell D. R., Jr, Bopp B. L., Fielding M. The significance of bleeding patterns in Norplant implant users. Obstet Gynecol. 1991 Feb;77(2):256–260. doi: 10.1097/00006250-199102000-00018. [DOI] [PubMed] [Google Scholar]
  48. Shoupe D., Mishell D. R. Norplant: subdermal implant system for long-term contraception. Am J Obstet Gynecol. 1989 May;160(5 Pt 2):1286–1292. doi: 10.1016/s0002-9378(89)80014-6. [DOI] [PubMed] [Google Scholar]
  49. Soule H. D., Vazguez J., Long A., Albert S., Brennan M. A human cell line from a pleural effusion derived from a breast carcinoma. J Natl Cancer Inst. 1973 Nov;51(5):1409–1416. doi: 10.1093/jnci/51.5.1409. [DOI] [PubMed] [Google Scholar]
  50. Stadel B. V., Lai S. H., Schlesselman J. J., Murray P. Oral contraceptives and premenopausal breast cancer in nulliparous women. Contraception. 1988 Sep;38(3):287–299. doi: 10.1016/0010-7824(88)90101-1. [DOI] [PubMed] [Google Scholar]
  51. Stoll B. A. Progestin therapy of breast cancer: comparison of agents. Br Med J. 1967 Aug 5;3(5561):338–341. doi: 10.1136/bmj.3.5561.338. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Sutherland R. L., Hall R. E., Pang G. Y., Musgrove E. A., Clarke C. L. Effect of medroxyprogesterone acetate on proliferation and cell cycle kinetics of human mammary carcinoma cells. Cancer Res. 1988 Sep 15;48(18):5084–5091. [PubMed] [Google Scholar]
  53. Vu Hai M. T., Warembourg M., Milgrom E. Hormonal control of progesterone receptors. Ann N Y Acad Sci. 1977 Mar 11;286:199–209. doi: 10.1111/j.1749-6632.1977.tb29417.x. [DOI] [PubMed] [Google Scholar]
  54. Wakeling A. E., Bowler J. Biology and mode of action of pure antioestrogens. J Steroid Biochem. 1988;30(1-6):141–147. doi: 10.1016/0022-4731(88)90086-6. [DOI] [PubMed] [Google Scholar]
  55. Weiss N. S., Sayvetz T. A. Incidence of endometrial cancer in relation to the use of oral contraceptives. N Engl J Med. 1980 Mar 6;302(10):551–554. doi: 10.1056/NEJM198003063021004. [DOI] [PubMed] [Google Scholar]
  56. Wiseman R. A. Oral contraceptives and breast cancer rates. Lancet. 1983 Dec 17;2(8364):1415–1416. doi: 10.1016/s0140-6736(83)90937-6. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES