Exp Clin Endocrinol Diabetes 2005; 113(2): 127-132
DOI: 10.1055/s-2004-830556
Article

J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York

Progesterone but Not Estradiol 17β Potentiates Local GH Secretions by Hormone-Dependent Breast Cancer Explants. An In Vitro Study

T. Milewicz1 , E. L. Gregoraszczuk2 , K. Augustowska2 , J. Krzysiek1 , K. Sztefko3 , J. Ryś4
  • 1Department of Endocrinology and Fertility, Jagiellonian University, Krakow, Poland
  • 2Laboratory of Physiology and Toxicology of Reproduction, Department of Physiology, Institute of Zoology, Jagiellonian University, Krakow, Poland
  • 3Department of Clinical Biochemistry, Jagiellonian University, Krakow, Poland
  • 4Department of Oncology and Pathology; Collegium Medicum; Jagiellonian University, Krakow, Poland
Further Information

Publication History

Received: February 9, 2004 First decision: May 6, 2004

Accepted: September 9, 2004

Publication Date:
17 March 2005 (online)

Abstract

The aim of this study was to evaluate the effects of treatment of breast cancer explants with tamoxifen (TMX) or RU486 on GH secretory dynamics in the presence of exogenous estrogen (E2), progesterone (P4) or both. Explants obtained during surgery were divided according to their sex steroid hormone receptor status. P4 (10-7 M) or 17β-estradiol (10-5 M) or both were tested in vitro for their ability to induce hGH secretion and cell proliferation. TMX (10-7 M) was added to E2, RU486 (10-7 M) to P4, and both were applied to E2 plus P4-supplemented cultures. The stimulatory action of P4 on GH secretion was noted in hormone-dependent (ER+/PR+) but not in hormone-independent explants (ER-/PR-). RU486 did not abolish this effect. The stimulatory action of P4 on GH release was not parallel to the stimulation of cell proliferation. E2 alone was without effect on GH secretion by both types of breast cancer explants. Combined treatment with both steroids stimulated GH secretion and cell proliferation by (ER+/PR+) explants. Both TMX and RU486 reversed this effect on cell proliferation while only RU486 abolished augmentation of GH secretion. In none of the hormone-dependent breast cancers, the combined treatment with E2 and P4 had any effect on GH secretion and cell proliferation. Taken together, these results lead us to the hypothesis that P4 but not E2 potentiates local GH secretion by hormone-dependent breast cancer explants. The fact that RU486 reversed neither GH secretion nor cell proliferation in hormone-dependent explants indicates its non-receptor-mediated mechanism of action.

References

  • 1 Ahmed S A, Gogal R M, Walsh J E. A new rapid and simple non-radioactive assay to monitor and determine the proliferation of lymphocytes: an alternative to [3H] thymidine incorporation assay.  J Immunol Methods. 1994;  170 211-224
  • 2 Baldini E, Giannessi P G, Gardin G, Alama A, Minuto F, Barreca A, Conte P F. In vivo cytokinetic effects of recombinant human growth hormone (rhGH) in patients with advanced breast carcinoma.  J Biol Regul Homeost Agents. 1994;  8 113-116
  • 3 Beral V. Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study.  Lancet. 2003;  362 419-427
  • 4 Bontenbal M, Foekens J A, Lamberts S W, de Jong F H, van Putten W L, Braun H J, Burghouts J T, van der Linden G H, Klijn J G. Feasibility, endocrine and anti-tumor effects of a triple endocrine therapy with tamoxifen, a somatostatin analogue and an antiprolactin in post-menopausal metastatic breast cancer: a randomized study with long-term follow-up.  Br J Cancer. 1998;  77 115-122
  • 5 Bush T L, Whiteman M, Flaws J A. Hormone replacement therapy and breast cancer: a qualitative review.  Obstet Gynecol. 2001;  98 498-508
  • 6 Clarke R, Skaar T, Baumann K, Leonessa F, James M, Lippman J, Thompson E W, Freter C, Brunner N. Hormonal carcinogenesis in breast cancer: cellular and molecular studies of malignant progression.  Breast Cancer Res Treat. 1994;  31 237-248
  • 7 Clarke C L, Sutherland R L. Progestin regulation of cellular proliferation.  Endocr Rev. 1990;  11 266-301
  • 8 Croce M V, Colussi A G, Segal-Eiras A. Assessment of methods for primary tissue culture of human breast epithelia.  J Exp Clin Cancer Res. 1998;  17 19-26
  • 9 Dao T L, Sinha D K, Nemoto T, Patel J. Effect of estrogen and progesterone on cellular replication of human breast tumors.  Cancer Res. 1982;  42 359-362
  • 10 Dixon J M. Hormone replacement therapy: is it safe for breast cancer patients?.  MJA. 2002;  177 340-341
  • 11 Fries R, Mitsuhashi M. Quantification of mitogen induced human lymphocytes proliferation: comparison of alamarBlue assay to 3H-thymidine incorporation assay.  J Clin Lab Anal. 1995;  9 89-95
  • 12 Gebre-Medhin M, Kindblom L G, Wennbo H, Tornell J, Meis-Kindblom J M. Growth hormone receptor is expressed in human breast cancer.  Am J Pathol. 2001;  158 1217-1222
  • 13 Gregoraszczuk E L, Milewicz T, Kolodziejczyk J, Krzysiek J, Basta A, Sztefko K, Kurek S, Stachura J. Progesterone-induced secretion of growth hormone, insulin-like growth factor I and prolactin by human breast cancer explants.  Gynecol Endocrinol. 2001;  15 251-258
  • 14 Horwitz K B. The molecular biology of RU486. Is there a role for antiprogestins in the treatment of breast cancer?.  Endocr Rev. 1992;  13 146-163
  • 15 Ishikawa T, Inoue S, Kakinuma C, Kuwayama C, Hamada Y, Shibutani Y. Growth-stimulating effect of dienogest, a synthetic steroid, on rodent, canine, and primate mammary glands.  Toxicology. 2000;  151 91-101
  • 16 Kajdaniuk D, Marek B, Kos-Kudla B, Buntner B, Zwirska-Korczala K, Ostrowska Z, Nowak M. Growth hormone and its interactions with chosen parameters of hormonal state in pre-menopausal women after mastectomy for breast cancer on adjuvant chemotherapy.  Wiadomości Lekarskie. 2000;  53 238-283
  • 17 Kaulsay K K, Mertani H C, Tornell J, Morel G, Lee K O, Lobie P E. Autocrine stimulation of human mammary carcinoma cell proliferation by human growth hormone.  Exp Cell Res. 1999;  250 35-50
  • 18 Lange C A, Richer J K, Shen T, Horwitz K B. Convergence of progesterone and epidermal growth factor signaling in breast cancer. Potentiation of mitogen-activated protein kinase pathways.  J Biol Chem. 1998;  273 31308-31316
  • 19 Lange C A, Richer J K, Horwitz K B. Hypothesis: Progesterone primes breast cancer cells for cross-talk with proliferative or antiproliferative signals.  Mol Endocrinol. 1999;  13 29-36
  • 20 Lantinga-van Leeuwen I S, van Garderen E, Rutteman G R, Mol J A. Cloning and cellular localization of the canine progesterone receptor: co-localization with growth hormone in the mammary gland.  J Steroid Biochem Mol Biol. 2000;  75 219-228
  • 21 Leung K C, Doyle N, Ballesteros M, Sjogren K, Watts C K, Low T H, Leong G M, Ross R J, Ho K K. Estrogen inhibits GH signaling by suppressing GH-induced JAK2 phosphorylation, an effect mediated by SOCS-2.  Proc Natl Acad Sci USA. 2003;  100 1016-1021
  • 22 Lippman M, Bolan G, Huff K. The effects of glucocrticoids and progesterone on hormone-responsive human breast cancer in long-term tissue culture.  Cancer Res. 1976;  36 4602-4608
  • 23 Mandala M, Moro C, Ferretti G, Calabro M G, Nole F, Rocca A, Munzone E, Castro A, Curigliano G. Effect of tamoxifen on GH and IGF-1 serum level in stage I - II breast cancer patients.  Anticancer Res. 2001;  21 585-588
  • 24 Milewicz T, Kołodziejczyk J, Basta A, Kurek S, Sztefko K, Krzysiek J, Gregoraszczuk E L. Growth hormone (GH) induced local insulin-like growth factor I (IGF-I) secretion by human breast cancer explants.  Pol J Gynaecol Invest. 2001;  4 61-65
  • 25 Milewicz T, Kolodziejczyk J, Krzysiek J, Basta A, Sztefko K, Kurek S, Stachura J, Gregoraszczuk E L. Cyproterone, norethindrone, medroxyprogesterone and levonorgestrel are less potent local human growth hormone and insulin-like growth factor I secretion stimulators then progesterone in human breast cancer explants expressing the estrogen receptor.  Gynecol Endocrinol. 2002;  16 319-329
  • 27 Nakayama G R, Caton M C, Nova M P, Parandoosh Z. Assesment of the Alamar Blue assay for cellular growth and viability in vitro.  J Immunol Methods. 1997;  204 205-208
  • 28 Raafat A M, Hofseth L J, Haslam S Z. Proliferative effects of combination estrogen and progesterone replacement therapy on the normal postmenopausal mammary gland in a murine model.  Am J Obstet Gynecol. 2001;  184 340-349
  • 29 Richer J K, Lagne C A, Manning N G, Owen G, Powell R, Horwitz K B. Convergence of progesterone with growth factor and cytokine signalling in breast cancer. Progesterone receptors regulate signal transducers and activators of transcription expression and activity.  J Biol Chem. 1998;  273 31317-31326
  • 30 Ross R K, Paganini-Hill A, Wan P C, Pike M C. Effect of hormone replacement therapy on breast cancer risk: estrogen vs. estrogen plus progestin.  J Natl Cancer Inst. 2000;  92 328-332
  • 31 Rossouw J E, Anderson G L, Prentice R L, LaCroix A Z, Kooperberg C, Stefanick M L, Jackson R D, Beresford S A, Howard B V, Johnson K C, Kotchen J M, Ockene J. Writing group for the Women's Health Initiative Investigators . Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial.  JAMA. 2002;  288 321-333
  • 32 Schairer C, Lubin J, Troisi R, Sturgeon S, Brinton L, Hoover R. Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk.  JAMA. 2000;  284 691-694
  • 33 Swanson S M, Unterman T G. The growth hormone-deficient spontaneous dwarf rat is resistant to chemically induced mammary carcinogenesis.  Carcinogenesis. 2002;  23 977-982
  • 34 Tannenbaum G S, Gurd W, Lapointe M, Pollak M. Tamoxifen attenuates pulsatile growth hormone secretion: mediation in part by somatostatin.  Endocrinology. 1992;  130 3395-3401
  • 35 Vignon F, Bardon S, Chalbos D, Rochefort H. Antiestrogen effect of R5020, a synthetic progestin in human breast cancer cells in culture.  J Clin Endocrinol Metab. 1983;  56 1124-1130

Prof. Dr. Ewa L. Gregoraszczuk

Laboratory of Physiology and Toxicology of Reproduction, Department of Physiology, Institute of Zoology, Jagiellonian University

Ingardena 6

30-060 Krakow

Poland

Phone: + 48126632615

Fax: + 48 1 26 34 37 16

Email: greg@zuk.iż.uj.edu.pl

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