About this Journal Submit a Manuscript Table of Contents
BioMed Research International
Volume 2013 (2013), Article ID 290575, 9 pages
http://dx.doi.org/10.1155/2013/290575
Review Article

Progesterone and Related Compounds in Hepatocellular Carcinoma: Basic and Clinical Aspects

1Department of Medical Laboratory Sciences and Biotechnology, Fooyin University, Kaohsiung 83102, Taiwan
2Cancer Center and Division of General & Gastroenterological Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan
3Department of Pathology, Kaohsiung Armed Forces General Hospital, Kaohsiung 80284, Taiwan
4Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80756, Taiwan
5Division of Hepato-Pancreatico-Biliary Surgery, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan

Received 20 July 2012; Revised 20 December 2012; Accepted 26 December 2012

Academic Editor: Fátima Regina Mena Barreto Silva

Copyright © 2013 Yao-Tsung Yeh et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. D. M. Parkin, “Global cancer statistics in the year 2000,” Lancet Oncology, vol. 2, no. 9, pp. 533–543, 2001. View at Publisher · View at Google Scholar · View at Scopus
  2. H. B. El-Serag and K. L. Rudolph, “Hepatocellular carcinoma: epidemiology and molecular carcinogenesis,” Gastroenterology, vol. 132, no. 7, pp. 2557–2576, 2007. View at Publisher · View at Google Scholar · View at Scopus
  3. H. B. El-Serag, “Hepatocellular carcinoma,” New England Journal of Medicine, vol. 365, no. 12, pp. 1118–1127, 2011.
  4. H. B. El-Serag, “Epidemiology of hepatocellular carcinoma,” Clinics in Liver Disease, vol. 5, no. 1, pp. 87–107, 2001. View at Scopus
  5. L. A. Mucci, H. E. Kuper, R. Tamimi, P. Lagiou, E. Spanos, and D. Trichopoulos, “Age at menarche and age at menopause in relation to hepatocellular carcinoma in women,” British Journal of Obstetrics and Gynaecology, vol. 108, no. 3, pp. 291–294, 2001. View at Publisher · View at Google Scholar · View at Scopus
  6. H. B. El-Serag, “Hepatocellular carcinoma: an epidemiologic view,” Journal of Clinical Gastroenterology, vol. 35, no. 5, supplement 2, pp. S72–S78, 2002. View at Publisher · View at Google Scholar · View at Scopus
  7. J. Erdstein, S. Wisebord, S. Y. Mishkin, and S. Mishkin, “The effect of several sex steroid hormones on the growth rate of three morris hepatoma tumor lines,” Hepatology, vol. 9, no. 4, pp. 621–624, 1989. View at Scopus
  8. S. H. Yeh and P. J. Chen, “Gender disparity of hepatocellular carcinoma: the roles of sex hormones,” Oncology, vol. 78, no. 1, pp. 172–179, 2010. View at Publisher · View at Google Scholar · View at Scopus
  9. J. J. Mulvihill, R. L. Ridolfi, and F. R. Schultz, “Hepatic adenoma in Fanconi anemia treated with oxymetholone,” Journal of Pediatrics, vol. 87, no. 1, pp. 122–124, 1975. View at Scopus
  10. A. T. Meadows, J. L. Naiman, and M. Valdes Dapena, “Hepatoma associated with androgen therapy for aplastic anemia,” Journal of Pediatrics, vol. 84, no. 1, pp. 109–110, 1974. View at Scopus
  11. I. Shimizu, M. Yasuda, Y. Mizobuchi et al., “Suppressive effect of oestradiol on chemical hepatocarcinogenesis in rats,” Gut, vol. 42, no. 1, pp. 112–119, 1998. View at Scopus
  12. M. W. Yu, H. C. Chang, S. C. Chang et al., “Role of reproductive factors in hepatocellular carcinoma: impact on hepatitis B- and C-related risk,” Hepatology, vol. 38, no. 6, pp. 1393–1400, 2003. View at Publisher · View at Google Scholar · View at Scopus
  13. I. Shimizu, “Impact of oestrogens on the progression of liver disease,” Liver International, vol. 23, no. 1, pp. 63–69, 2003. View at Scopus
  14. L. Codes, T. Asselah, D. Cazals-Hatem et al., “Liver fibrosis in women with chronic hepatitis C: evidence for the negative role of the menopause and steatosis and the potential benefit of hormone replacement therapy,” Gut, vol. 56, no. 3, pp. 390–395, 2007. View at Publisher · View at Google Scholar · View at Scopus
  15. R. G. Simonetti, C. Camma, F. Fiorello, F. Politi, G. D'Amico, and L. Pagliaro, “Hepatocellular carcinoma. A worldwide problem and the major risk factors,” Digestive Diseases and Sciences, vol. 36, no. 7, pp. 962–972, 1991. View at Scopus
  16. G. Fattovich, T. Stroffolini, I. Zagni, and F. Donato, “Hepatocellular carcinoma in cirrhosis: incidence and risk factors,” Gastroenterology, vol. 127, pp. S35–S50, 2004. View at Publisher · View at Google Scholar · View at Scopus
  17. J. Guechot, N. Peigney, F. Ballet, M. Vaubourdolle, J. Giboudeau, and R. Poupon, “Sex hormone imbalance in male alcoholic cirrhotic patients with and without hepatocellular carcinoma,” Cancer, vol. 62, no. 4, pp. 760–762, 1988. View at Scopus
  18. F. Farinati, N. De Maria, C. Marafin, S. Fagiuoli, G. D. Libera, and R. Naccarato, “Hepatocellular carcinoma in alcoholic cirrhosis: is sex hormone imbalance a pathogenetic factor,” European Journal of Gastroenterology and Hepatology, vol. 7, no. 2, pp. 145–150, 1995. View at Scopus
  19. N. L. Weigel and N. L. Moore, “Steroid receptor phosphorylation: a key modulator of multiple receptor functions,” Molecular Endocrinology, vol. 21, no. 10, pp. 2311–2319, 2007. View at Publisher · View at Google Scholar · View at Scopus
  20. V. Stanisić, D. M. Lonard, and B. W. O'Malley, “Modulation of steroid hormone receptor activity,” Progress in Brain Research, vol. 181, pp. 153–176, 2010. View at Scopus
  21. A. Migliaccio, G. Castoria, and F. Auricchio, “Src-dependent signalling pathway regulation by sex-steroid hormones: therapeutic implications,” International Journal of Biochemistry and Cell Biology, vol. 39, no. 7-8, pp. 1343–1348, 2007. View at Publisher · View at Google Scholar · View at Scopus
  22. W. L. Ma, C. L. Hsu, C. C. Yeh, et al., “Hepatic androgen receptor suppresses hepatocellular carcinoma metastasis through modulation of cell migration and anoikis,” Hepatology, vol. 56, no. 1, pp. 176–185, 2012.
  23. N. Nagasue, H. Kohno, Y. C. Chang et al., “Clinicopathologic comparisons between estrogen receptor-positive and -negative hepatocellular carcinomas,” Annals of Surgery, vol. 212, no. 2, pp. 150–154, 1990. View at Scopus
  24. N. Nagasue, H. Kohno, A. Yamanoi, T. Kimoto, Y. C. Chang, and T. Nakamura, “Progesterone receptor in hepatocellular carcinoma: correlation with androgen and estrogen receptors,” Cancer, vol. 67, no. 10, pp. 2501–2505, 1991. View at Scopus
  25. S. Mandlekar and A. N. T. Kong, “Mechanisms of tamoxifen-induced apoptosis,” Apoptosis, vol. 6, no. 6, pp. 469–477, 2001. View at Publisher · View at Google Scholar · View at Scopus
  26. R. Guo, T. Wang, H. Shen et al., “Involvement of mTOR and survivin inhibition in tamoxifen-induced apoptosis in human hepatoblastoma cell line HepG2,” Biomedicine and Pharmacotherapy, vol. 64, no. 4, pp. 249–253, 2010. View at Publisher · View at Google Scholar · View at Scopus
  27. E. Villa, A. Dugani, E. Fantoni et al., “Type of estrogen receptor determines response to antiestrogen therapy,” Cancer Research, vol. 56, no. 17, pp. 3883–3885, 1996. View at Scopus
  28. E. P. Gelmann, “Tamoxifen for the treatment of malignancies other than breast and endometrial carcinoma,” Seminars in Oncology, vol. 24, no. 1, supplement, pp. S1–S1, 1997. View at Scopus
  29. P. K. H. Chow, B. C. Tai, C. K. Tan et al., “High-dose tamoxifen in the treatment of inoperable hepatocellular carcinoma: a multicenter randomized controlled trial,” Hepatology, vol. 36, no. 5, pp. 1221–1226, 2002. View at Publisher · View at Google Scholar · View at Scopus
  30. E. Villa, A. Colantoni, A. Grottola et al., “Variant estrogen receptors and their role in liver disease,” Molecular and Cellular Endocrinology, vol. 193, no. 1-2, pp. 65–69, 2002. View at Publisher · View at Google Scholar · View at Scopus
  31. V. Boonyaratanakornkit, E. McGowan, L. Sherman, M. A. Mancini, B. J. Cheskis, and D. P. Edwards, “The role of extranuclear signaling actions of progesterone receptor in mediating progesterone regulation of gene expression and the cell cycle,” Molecular Endocrinology, vol. 21, no. 2, pp. 359–375, 2007. View at Publisher · View at Google Scholar · View at Scopus
  32. E. Villa, I. Ferretti, A. Grottola et al., “Hormonal therapy with megestrol in inoperable hepatocellular carcinoma characterized by variant oestrogen receptors,” British Journal of Cancer, vol. 84, no. 7, pp. 881–885, 2001. View at Publisher · View at Google Scholar · View at Scopus
  33. K. Zhang and P. K. H. Chow, “The effect of megestrol acetate on growth of HepG2 cells in vitro and in vivo,” Clinical Cancer Research, vol. 10, no. 15, pp. 5226–5232, 2004. View at Publisher · View at Google Scholar · View at Scopus
  34. M. Di Maio, B. Daniele, S. Pignata et al., “Is human hepatocellular carcinoma a hormone-responsive tumor?” World Journal of Gastroenterology, vol. 14, no. 11, pp. 1682–1689, 2008. View at Publisher · View at Google Scholar · View at Scopus
  35. Y. Chao, W. K. Chan, S. S. Wang, et al., “Phase II study of megestrol acetate in the treatment of hepatocellular carcinoma,” Journal of Gastroenterology and Hepatology, vol. 12, no. 4, pp. 277–281, 1997.
  36. P. K. Chow, D. Machin, Y. Chen, et al., “Randomised double-blind trial of megestrol acetate vs placebo in treatment-naive advanced hepatocellular carcinoma,” British Journal of Cancer, vol. 105, no. 7, pp. 945–952, 2011.
  37. X. D. Fu, M. S. Giretti, C. Baldacci et al., “Extra-nuclear signaling of progesterone receptor to breast cancer cell movement and invasion through the actin cytoskeleton,” PLoS ONE, vol. 3, no. 7, Article ID e2790, 2008. View at Publisher · View at Google Scholar · View at Scopus
  38. F. Zeze, S. Onami, and K. Osato, “Experimental studies on endocrine therapy for rat hepatocellular carcinoma,” Nippon Geka Gakkai Zasshi, vol. 96, no. 11, pp. 760–765, 1995. View at Scopus
  39. S. N. Wang, Y. T. Yeh, S. F. Yang, et al., “Potential role of leptin expression in hepatocellular carcinoma,” Journal of Clinical Pathology, vol. 59, no. 9, pp. 930–934, 2006.
  40. J. Uchino, Y. Une, Y. Sato, H. Gondo, Y. Nakajima, and N. Sato, “Chemohormonal therapy of unresectable hepatocellular carcinoma,” American Journal of Clinical Oncology, vol. 16, no. 3, pp. 206–209, 1993. View at Scopus
  41. M. B. Aufrere and H. Benson, “Progesterone: an overview and recent advances,” Journal of Pharmaceutical Sciences, vol. 65, no. 6, pp. 783–800, 1976. View at Scopus
  42. Z. H. Chakmakjian and N. Y. Zachariag, “Bioavailability of progesterone with different modes of administration,” Journal of Reproductive Medicine for the Obstetrician and Gynecologist, vol. 32, no. 6, pp. 443–448, 1987. View at Scopus
  43. H. Adlercreutz and F. Martin, “Biliary excretion and intestinal metabolism of progesterone and estrogens in man,” Journal of Steroid Biochemistry, vol. 13, no. 2, pp. 231–244, 1980. View at Publisher · View at Google Scholar · View at Scopus
  44. M. I. Whitehead, P. T. Townsend, and D. K. Gill, “Absorption and metabolism of oral progesterone,” British Medical Journal, vol. 280, no. 6217, pp. 825–827, 1980. View at Scopus
  45. J. G. Wiswell and L. T. Samuels, “The metabolism of progesterone by liver tissue in vitro,” The Journal of Biological Chemistry, vol. 201, no. 1, pp. 155–160, 1953. View at Scopus
  46. L. M. Atherden, “Progesterone metabolism; investigation of the products of metabolism with human liver in vitro,” The Biochemical Journal, vol. 71, no. 2, pp. 411–415, 1959. View at Scopus
  47. D. L. Berliner and W. G. Wiest, “The extra-hepatic metabolism of progesterone in rats,” The Journal of Biological Chemistry, vol. 221, no. 1, pp. 449–459, 1956. View at Scopus
  48. W. G. Wiest, “The metabolism of progesterone to delta4-pregnen-20alpha-ol-3-one in eviscerated female rats,” The Journal of Biological Chemistry, vol. 221, no. 1, pp. 461–467, 1956. View at Scopus
  49. J. P. Wiebe, “Progesterone metabolites in breast cancer,” Endocrine-Related Cancer, vol. 13, no. 3, pp. 717–738, 2006. View at Publisher · View at Google Scholar · View at Scopus
  50. S. Sasagawa, Y. Shimizu, H. Kami et al., “Dienogest is a selective progesterone receptor agonist in transactivation analysis with potent oral endometrial activity due to its efficient pharmacokinetic profile,” Steroids, vol. 73, no. 2, pp. 222–231, 2008. View at Publisher · View at Google Scholar · View at Scopus
  51. J. A. Kemppainen, E. Langley, C. I. Wong, K. Bobseine, W. R. Kelce, and E. M. Wilson, “Distinguishing androgen receptor agonists and antagonists: distinct mechanisms of activation by medroxyprogesterone acetate and dihydrotestosterone,” Molecular Endocrinology, vol. 13, no. 3, pp. 440–454, 1999. View at Scopus
  52. H. Kuhl, “Pharmacology of estrogens and progestogens: influence of different routes of administration,” Climacteric, vol. 8, no. 1, supplement, pp. 3–63, 2005. View at Publisher · View at Google Scholar · View at Scopus
  53. A. O. Mueck and R. Sitruk-Ware, “Nomegestrol acetate, a novel progestogen for oral contraception,” Steroids, vol. 76, no. 6, pp. 531–539, 2011. View at Publisher · View at Google Scholar · View at Scopus
  54. D. Africander, N. Verhoog, and J. P. Hapgood, “Molecular mechanisms of steroid receptor-mediated actions by synthetic progestins used in HRT and contraception,” Steroids, vol. 76, no. 7, pp. 636–652, 2011. View at Publisher · View at Google Scholar · View at Scopus
  55. J. Dinny Graham and C. L. Clarke, “Physiological action of progesterone in target tissues,” Endocrine Reviews, vol. 18, no. 4, pp. 502–519, 1997. View at Publisher · View at Google Scholar · View at Scopus
  56. B. A. Cooke and D. K. Vallance, “Metabolism of megestrol acetate and related progesterone analogues by liver preparations in vitro,” Biochemical Journal, vol. 97, no. 3, pp. 672–677, 1965. View at Scopus
  57. F. A. G. Teulings, H. A. Van Gilse, and M. S. Henkelman, “Estrogen, androgen, glucocorticoid, and progesterone receptors in progestin-induced regression of human breast cancer,” Cancer Research, vol. 40, no. 7, pp. 2557–2561, 1980. View at Scopus
  58. A. P. López, M. Roqué I Figuls, G. U. Cuchi et al., “Systematic review of megestrol acetate in the treatment of anorexia-cachexia syndrome,” Journal of Pain and Symptom Management, vol. 27, no. 4, pp. 360–369, 2004. View at Publisher · View at Google Scholar · View at Scopus
  59. S. P. Langdon, H. Gabra, J. M. S. Bartlett et al., “Functionality of the progesterone receptor in ovarian cancer and its regulation by estrogen,” Clinical Cancer Research, vol. 4, no. 9, pp. 2245–2251, 1998. View at Scopus
  60. P. G. Satyaswaroop, C. L. Clarke, R. J. Zaino, and R. Mortel, “Apparent resistance in human endometrial carcinoma during combination treatment with tamoxifen and progestin may result from desensitization following downregulation of tumor progesterone receptor,” Cancer Letters, vol. 62, no. 2, pp. 107–114, 1992. View at Publisher · View at Google Scholar · View at Scopus
  61. R. J. Zaino, P. G. Satyaswaroop, and R. Mortel, “Hormonal therapy of human endometrial adenocarcinoma in a nude mouse model,” Cancer Research, vol. 45, no. 2, pp. 539–541, 1985. View at Scopus
  62. L. E. Tisell and H. Salander, “Androgenic properties and adrenal depressant activity of megestrol acetate observed in castrated male rats,” Acta Endocrinologica, vol. 78, no. 2, pp. 316–324, 1975. View at Scopus
  63. K. Pazol, M. E. Wilson, and K. Wallen, “Medroxyprogesterone acetate antagonizes the effects of estrogen treatment on social and sexual behavior in female macaques,” Journal of Clinical Endocrinology and Metabolism, vol. 89, no. 6, pp. 2998–3006, 2004. View at Publisher · View at Google Scholar · View at Scopus
  64. R. Poulin, D. Baker, D. Poirier, and F. Labrie, “Androgen and glucocorticoid receptor-mediated inhibition of cell proliferation by medroxyprogesterone acetate in ZR-75-1 human breast cancer cells,” Breast Cancer Research and Treatment, vol. 13, no. 2, pp. 161–172, 1989. View at Scopus
  65. S. N. Birrell, R. E. Hall, and W. D. Tilley, “Role of the androgen receptor in human breast cancer,” Journal of Mammary Gland Biology and Neoplasia, vol. 3, no. 1, pp. 95–103, 1998. View at Scopus
  66. G. Buchanan, S. N. Birrell, A. A. Peters et al., “Decreased androgen receptor levels and receptor function in breast cancer contribute to the failure of response to medroxyprogesterone acetate,” Cancer Research, vol. 65, no. 18, pp. 8487–8496, 2005. View at Publisher · View at Google Scholar · View at Scopus
  67. B. Ettinger and I. M. Golditch, “Medroxyprogesterone acetate for the evaluation of hypertestosteronism in hirsute women,” Fertility and Sterility, vol. 28, no. 12, pp. 1285–1288, 1977. View at Scopus
  68. R. F. Correa De Oliveira, L. P. Novaes, and M. B. Lima, “A new treatment for hirsutism,” Annals of Internal Medicine, vol. 83, no. 6, pp. 817–819, 1975. View at Scopus
  69. R. A. Richman, L. E. Underwood, F. S. French, and J. J. Van Wyk, “Adverse effects of large doses ofmedroxyprogesterone (MPA) in idiopathic isosexual precocity,” The Journal of Pediatrics, vol. 79, no. 6, pp. 963–971, 1971. View at Scopus
  70. D. P. Edwards, S. E. Wardell, and V. Boonyaratanakornkit, “Progesterone receptor interacting coregulatory proteins and cross talk with cell signaling pathways,” Journal of Steroid Biochemistry and Molecular Biology, vol. 83, no. 1–5, pp. 173–186, 2002. View at Publisher · View at Google Scholar · View at Scopus
  71. P. Kastner, A. Krust, B. Turcotte et al., “Two distinct estrogen-regulated promoters generate transcripts encoding the two functionally different human progesterone receptor forms A and B,” EMBO Journal, vol. 9, no. 5, pp. 1603–1614, 1990. View at Scopus
  72. M. J. Tsai and B. W. O'Malley, “Molecular mechanisms of action of steroid/thyroid receptor superfamily members,” Annual Review of Biochemistry, vol. 63, pp. 451–486, 1994. View at Scopus
  73. J. Cheung and D. F. Smith, “Molecular chaperone interactions with steroid receptors: an update,” Molecular Endocrinology, vol. 14, no. 7, pp. 939–946, 2000. View at Publisher · View at Google Scholar · View at Scopus
  74. S. R. Hammes and E. R. Levin, “Minireview: recent advances in extranuclear steroid receptor actions,” Endocrinology, vol. 152, no. 12, pp. 4489–4495, 2011.
  75. C. Lindet, F. Révillion, V. Lhotellier, L. Hornez, J. P. Peyrat, and J. Bonneterre, “Relationships between progesterone receptor isoforms and the HER/ErbB receptors and ligands network in 299 primary breast cancers,” The International Journal of Biological Markers, vol. 27, no. 2, pp. e111–e117, 2012.
  76. D. X. Wen, Y. F. Xu, D. E. Mais, M. E. Goldman, and D. P. McDonnell, “The A and B isoforms of the human progesterone receptor operate through distinct signaling pathways within target cells,” Molecular and Cellular Biology, vol. 14, no. 12, pp. 8356–8364, 1994. View at Scopus
  77. E. Vegeto, M. M. Shahbaz, D. X. Wen, M. E. Goldman, B. W. O'Malley, and D. P. McDonnell, “Human progesterone receptor A form is a cell- and promoter-specific repressor of human progesterone receptor B function,” Molecular Endocrinology, vol. 7, no. 10, pp. 1244–1255, 1993. View at Publisher · View at Google Scholar · View at Scopus
  78. D. P. Edwards, “Regulation of signal transduction pathways by estrogen and progesterone,” Annual Review of Physiology, vol. 67, pp. 335–376, 2005. View at Publisher · View at Google Scholar · View at Scopus
  79. V. Boonyaratanakornkit, M. P. Scott, V. Ribon et al., “Progesterone receptor contains a proline-rich motif that directly interacts with SH3 domains and activates c-Src family tyrosine kinases,” Molecular Cell, vol. 8, no. 2, pp. 269–280, 2001. View at Publisher · View at Google Scholar · View at Scopus
  80. G. Castoria, M. V. Barone, M. Di Domenico et al., “Non-transcriptional action of oestradiol and progestin triggers DNA synthesis,” EMBO Journal, vol. 18, no. 9, pp. 2500–2510, 1999. View at Publisher · View at Google Scholar · View at Scopus
  81. Z. Li, E. B. Watkins, H. Liu, A. G. Chittiboyina, P. B. Carvalho, and M. A. Avery, “1,3-Diaxially substituted trans-decalins: potential nonsteroidal human progesterone receptor inhibitors,” Journal of Organic Chemistry, vol. 73, no. 19, pp. 7764–7767, 2008. View at Publisher · View at Google Scholar · View at Scopus
  82. A. Skildum, E. Faivre, and C. A. Lange, “Progesterone receptors induce cell cycle progression via activation of mitogen-activated protein kinases,” Molecular Endocrinology, vol. 19, no. 2, pp. 327–339, 2005. View at Publisher · View at Google Scholar · View at Scopus
  83. E. J. Faivre and C. A. Lange, “Progesterone receptors upregulate Wnt-1 to induce epidermal growth factor receptor transactivation and c-Src-dependent sustained activation of Erk1/2 mitogen-activated protein kinase in breast cancer cells,” Molecular and Cellular Biology, vol. 27, no. 2, pp. 466–480, 2007. View at Publisher · View at Google Scholar · View at Scopus
  84. C. Ballaré, M. Uhrig, T. Bechtold et al., “Two domains of the progesterone receptor interact with the estrogen receptor and are required for progesterone activation of the c-Src/Erk pathway in mammalian cells,” Molecular and Cellular Biology, vol. 23, no. 6, pp. 1994–2008, 2003. View at Publisher · View at Google Scholar · View at Scopus
  85. R. P. Carnevale, C. J. Proietti, M. Salatino et al., “Progestin effects on breast cancer cell proliferation, proteases activation, and in vivo development of metastatic phenotype all depend on progesterone receptor capacity to activate cytoplasmic signaling pathways,” Molecular Endocrinology, vol. 21, no. 6, pp. 1335–1358, 2007. View at Publisher · View at Google Scholar · View at Scopus
  86. C. Proietti, M. Salatino, C. Rosemblit et al., “Progestins induce transcriptional activation of signal transducer and activator of transcription 3 (Stat3) via a Jak- and Src-dependent mechanism in breast cancer cells,” Molecular and Cellular Biology, vol. 25, no. 12, pp. 4826–4840, 2005. View at Publisher · View at Google Scholar · View at Scopus
  87. J. M. Llovet, A. M. Di Bisceglie, J. Bruix et al., “Design and endpoints of clinical trials in hepatocellular carcinoma,” Journal of the National Cancer Institute, vol. 100, no. 10, pp. 698–711, 2008. View at Publisher · View at Google Scholar · View at Scopus
  88. T. Itagaki, I. Shimizu, and X. Cheng, “Opposing effects of oestradiol and progesterone on intracellular pathways and activation processes in the oxidative stress induced activation of cultured rat hepatic stellate cells,” Gut, vol. 54, no. 12, pp. 1782–1789, 2005. View at Publisher · View at Google Scholar · View at Scopus
  89. V. Boonyaratanakornkit, Y. Bi, M. Rudd, and D. P. Edwards, “The role and mechanism of progesterone receptor activation of extra-nuclear signaling pathways in regulating gene transcription and cell cycle progression,” Steroids, vol. 73, no. 9-10, pp. 922–928, 2008. View at Publisher · View at Google Scholar · View at Scopus
  90. Y. Ito, H. Kawakatsu, T. Takeda et al., “Activation of c-Src gene product in hepatocellular carcinoma is highly correlated with the indices of early stage phenotype,” Journal of Hepatology, vol. 35, no. 1, pp. 68–73, 2001. View at Publisher · View at Google Scholar · View at Scopus
  91. E. Falkenstein, M. Heck, D. Gerdes et al., “Specific progesterone binding to a membrane protein and related nongenomic effects on Ca2+-fluxes in sperm,” Endocrinology, vol. 140, no. 12, pp. 5999–6002, 1999. View at Scopus
  92. J. J. Peluso, “Progesterone signaling mediated through progesterone receptor membrane component-1 in ovarian cells with special emphasis on ovarian cancer,” Steroids, vol. 76, no. 9, pp. 903–909, 2011. View at Publisher · View at Google Scholar · View at Scopus
  93. K. T. Wheeler, L. M. Wang, C. A. Wallen et al., “Sigma-2 receptors as a biomarker of proliferation in solid tumours,” British Journal of Cancer, vol. 82, no. 6, pp. 1223–1232, 2000. View at Scopus
  94. J. J. Peluso, J. Romak, and X. Liu, “Progesterone receptor membrane component-1 (PGRMC1) is the mediator of progesterone's antiapoptotic action in spontaneously immortalized granulosa cells as revealed by PGRMC1 small interfering ribonucleic acid treatment and functional analysis of PGRMC1 mutations,” Endocrinology, vol. 149, no. 2, pp. 534–543, 2008. View at Publisher · View at Google Scholar · View at Scopus
  95. H. J. Rohe, I. S. Ahmed, K. E. Twist, and R. J. Craven, “PGRMC1 (progesterone receptor membrane component 1): a targetable protein with multiple functions in steroid signaling, P450 activation and drug binding,” Pharmacology and Therapeutics, vol. 121, no. 1, pp. 14–19, 2009. View at Publisher · View at Google Scholar · View at Scopus
  96. Y. Toyoda, S. Endo, K. Tsuneyama, et al., “Mechanism of exacerbative effect of progesterone on drug-induced liver injury,” Toxicological Sciences, vol. 126, no. 1, pp. 16–27, 2012.
  97. S. Lundgren, P. E. Lonning, E. Utaaker, A. Aakvaag, and S. Kvinnsland, “Influence of progestins on serum hormone levels in postmenopausal women with advanced breast cancer—I. General findings,” Journal of Steroid Biochemistry, vol. 36, no. 1-2, pp. 99–104, 1990. View at Publisher · View at Google Scholar · View at Scopus
  98. J. Geller, J. Albert, and S. Geller, “Acute therapy with megestrol acetate decreases nuclear and cytosol androgen receptors in human BPH tissue,” Prostate, vol. 3, no. 1, pp. 11–15, 1982. View at Scopus
  99. G. R. Blumenschein, “The role of progestins in the treatment of breast cancer,” Seminars in Oncology, vol. 10, no. 4, supplement, pp. 7–10, 1983. View at Scopus
  100. C. Eil and S. K. Edelson, “The use of human skin fibroblasts to obtain potency estimates of drug binding to androgen receptors,” Journal of Clinical Endocrinology and Metabolism, vol. 59, no. 1, pp. 51–55, 1984. View at Scopus
  101. I. A. Luthy, D. J. Begin, and F. Labrie, “Androgenic activity of synthetic progestins and spironolactone in androgen-sensitive mouse mammary carcinoma (Shionogi) cells in culture,” Journal of Steroid Biochemistry, vol. 31, no. 5, pp. 845–852, 1988. View at Scopus
  102. P. Poyet and F. Labrie, “Comparison of the antiandrogenic/androgenic activities of flutamide, cyproterone acetate and megestrol acetate,” Molecular and Cellular Endocrinology, vol. 42, no. 3, pp. 283–288, 1985. View at Publisher · View at Google Scholar · View at Scopus
  103. D. J. Farrar, “Megestrol acetate: promises and pitfalls,” AIDS Patient Care and STDs, vol. 13, no. 3, pp. 149–152, 1999. View at Scopus
  104. A. A. Martoni, A. Bernardi, and S. Quercia, “Trastuzumab plus estrogen suppression as salvage treatment in a case of liver failure due to metastatic breast cancer,” Anticancer Research, vol. 26, no. 5 B, pp. 3739–3744, 2006. View at Scopus
  105. A. E. Schindler, C. Campagnoli, R. Druckmann et al., “Classification and pharmacology of progestins,” Maturitas, vol. 46, no. 1, supplement, pp. S7–S16, 2003. View at Publisher · View at Google Scholar · View at Scopus
  106. M. Kalra, J. Mayes, S. Assefa, A. K. Kaul, and R. Kaul, “Role of sex steroid receptors in pathobiology of hepatocellular carcinoma,” World Journal of Gastroenterology, vol. 14, no. 39, pp. 5945–5961, 2008. View at Publisher · View at Google Scholar · View at Scopus