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Estrogens and prostate cancer

Abstract

Background

Hormonal influences such as androgens and estrogens are known contributors in the development and progression of prostate cancer (CaP). While much of the research to the hormonal nature of CaP has focused on androgens, estrogens also have critical roles in CaP development, physiology as well as a potential therapeutic intervention.

Methods

In this review, we provide a critical literature review of the current basic science and clinical evidence for the interaction between estrogens and CaP.

Results

Estrogenic influences in CaP include synthetic, endogenous, fungi and plant-derived compounds, and represent a family of sex hormones, which cross hydrophobic cell membranes and bind to membrane-associated receptors and estrogen receptors that localize to the nucleus triggering changes in gene expression in various organ systems.

Conclusions

Estrogens represent a under-recognized contributor in CaP development and progression. Further research in this topic may provide opportunities for identification of environmental influencers as well as providing novel therapeutic targets in the treatment of CaP.

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References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics. CA Cancer J Clin. 2016;66:7–30.

    PubMed  Google Scholar 

  2. Huggins CH. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res. 1941;1:293–7.

    CAS  Google Scholar 

  3. Pagliarulo V, et al. Contemporary role of androgen deprivation therapy for prostate cancer. Eur Urol. 2012;61:11–25.

    CAS  PubMed  Google Scholar 

  4. Lorand T, Vigh E, Garai J. Hormonal action of plant derived and anthropogenic non-steroidal estrogenic compounds: phytoestrogens and xenoestrogens. Curr Med Chem. 2010;17:3542–74.

    CAS  PubMed  Google Scholar 

  5. Lee HR, Kim TH, Choi KC. Functions and physiological roles of two types of estrogen receptors, ERalpha and ERbeta, identified by estrogen receptor knockout mouse. Lab Anim Res. 2012;28:71–6.

    PubMed  PubMed Central  Google Scholar 

  6. Yeh CR, Da J, Song W, Fazili A, Yeh S. Estrogen receptors in prostate development and cancer. Am J Clin Exp Urol. 2014;2:161–8.

    PubMed  PubMed Central  Google Scholar 

  7. Rago V, Romeo F, Giordano F, Ferraro A, Carpino A. Identification of the G protein-coupled estrogen receptor (GPER) in human prostate: expression site of the estrogen receptor in the benign and neoplastic gland. Andrology. 2016;4:121–7.

    PubMed  Google Scholar 

  8. Heldring N, et al. Estrogen receptors: how do they signal and what are their targets. Physiol Rev. 2007;87:905–31.

    CAS  PubMed  Google Scholar 

  9. Deroo BJ, Korach KS. Estrogen receptors and human disease. J Clin Invest. 2006;116:561–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Mauvais-Jarvis F, Clegg DJ, Hevener AL. The role of estrogens in control of energy balance and glucose homeostasis. Endocr Rev. 2013;34:309–38.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Driscoll SG, Taylor SH. Effects of prenatal maternal estrogen on the male urogenital system. Obstet Gynecol. 1980;56:537–42.

    CAS  PubMed  Google Scholar 

  12. Ho SM, Tang WY, Belmonte de Frausto J, Prins GS. Developmental exposure to estradiol and bisphenol A increases susceptibility to prostate carcinogenesis and epigenetically regulates phosphodiesterase type 4 variant 4. Cancer Res. 2006;66:5624–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Wibowo E, Schellhammer P, Wassersug RJ. Role of estrogen in normal male function: clinical implications for patients with prostate cancer on androgen deprivation therapy. J Urol. 2011;185:17–23.

    CAS  PubMed  Google Scholar 

  14. Cooke BM. Steroid-dependent plasticity in the medial amygdala. Neuroscience. 2006;138:997–1005.

    CAS  PubMed  Google Scholar 

  15. Hofman MA, Swaab DF. The sexually dimorphic nucleus of the preoptic area in the human brain: a comparative morphometric study. J Anat. 1989;164:55–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Nelles JL, Hu WY, Prins GS. Estrogen action and prostate cancer. Expert Rev Endocrinol Metab. 2011;6:437–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Hu WY, et al. Estrogen-initiated transformation of prostate epithelium derived from normal human prostate stem-progenitor cells. Endocrinology. 2011;152:2150–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Bardin A, Boulle N, Lazennec G, Vignon F, Pujol P. Loss of ERbeta expression as a common step in estrogen-dependent tumor progression. Endocr Relat Cancer. 2004;11:537–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Levakov AF, et al. The expression and localization of estrogen receptor beta in hyperplastic and neoplastic prostate lesions. Vojnosanit Pregl. 2015;72:906–13.

    PubMed  Google Scholar 

  20. Mishra S., et al. Estrogen and estrogen receptor alpha promotes malignancy and osteoblastic tumorigenesis in prostate cancer. Oncotarget. 2016;6:44388–402.

  21. Attia DM, Ederveen AG. Opposing roles of ERalpha and ERbeta in the genesis and progression of adenocarcinoma in the rat ventral prostate. Prostate. 2012;72:1013–22.

    CAS  PubMed  Google Scholar 

  22. Pupo M, Maggiolini M, Musti AM. GPER mediates non-genomic effects of estrogen. Methods Mol Biol. 2016;1366:471–88.

    CAS  PubMed  Google Scholar 

  23. Prins GS, Birch L, Tang WY, Ho SM. Developmental estrogen exposures predispose to prostate carcinogenesis with aging. Reprod Toxicol. 2007;23:374–82.

    CAS  PubMed  Google Scholar 

  24. Prins GS, Tang WY, Belmonte J, Ho SM. Perinatal exposure to oestradiol and bisphenol A alters the prostate epigenome and increases susceptibility to carcinogenesis. Basic Clin Pharmacol Toxicol. 2008;102:134–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Bosland MC. The role of estrogens in prostate carcinogenesis: a rationale for chemoprevention. Rev Urol. 2005;7(Suppl 3):S4–S10.

    PubMed  PubMed Central  Google Scholar 

  26. Bosland MC. A perspective on the role of estrogen in hormone-induced prostate carcinogenesis. Cancer Lett. 2013;334:28–33.

    CAS  PubMed  Google Scholar 

  27. Prins GS, Ho SM. Early-life estrogens and prostate cancer in an animal model. J Dev Orig Health Dis. 2010;1:365–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Huang L, Pu Y, Hepps D, Danielpour D, Prins GS. Posterior Hox gene expression and differential androgen regulation in the developing and adult rat prostate lobes. Endocrinology. 2007;148:1235–45.

    CAS  PubMed  Google Scholar 

  29. Huang L, Pu Y, Alam S, Birch L, Prins GS. The role of Fgf10 signaling in branching morphogenesis and gene expression of the rat prostate gland: lobe-specific suppression by neonatal estrogens. Dev Biol. 2005;278:396–414.

    CAS  PubMed  Google Scholar 

  30. Garnick MB. Hormonal therapy in the management of prostate cancer: from Huggins to the present. Urology. 1997;49:5–15.

    CAS  PubMed  Google Scholar 

  31. Melnick S, Cole P, Anderson D, Herbst A. Rates and risks of diethylstilbestrol-related clear-cell adenocarcinoma of the vagina and cervix. An update. N Engl J Med. 1987;316:514–6.

    CAS  PubMed  Google Scholar 

  32. Gill WB, et al. Association of diethylstilbestrol exposure in utero with cryptorchidism, testicular hypoplasia and semen abnormalities. J Urol. 1979;122:36–9.

    CAS  PubMed  Google Scholar 

  33. Arai Y, Chen CY, Nishizuka Y. Cancer development in male reproductive tract in rats given diethylstilbestrol at neonatal age. Gan . 1978;69:861–2.

    PubMed  Google Scholar 

  34. Ramos JG, et al. Prenatal exposure to low doses of bisphenol A alters the periductal stroma and glandular cell function in the rat ventral prostate. Biol Reprod. 2001;65:1271–7.

    CAS  PubMed  Google Scholar 

  35. Prins GS, et al. Prostate cancer risk and DNA methylation signatures in aging rats following developmental BPA exposure: a dose-response analysis. Environ Health Perspect. 2017;125:077007.

    PubMed  PubMed Central  Google Scholar 

  36. Tarapore P, et al. Exposure to bisphenol A correlates with early-onset prostate cancer and promotes centrosome amplification and anchorage-independent growth in vitro. PLoS ONE. 2014;9:e90332.

    PubMed  PubMed Central  Google Scholar 

  37. Prins GS, et al. Bisphenol A promotes human prostate stem-progenitor cell self-renewal and increases in vivo carcinogenesis in human prostate epithelium. Endocrinology. 2014;155:805–17.

    PubMed  PubMed Central  Google Scholar 

  38. Ho SM, Lee MT, Lam HM, Leung YK. Estrogens and prostate cancer: etiology, mediators, prevention, and management. Endocrinol Metab Clin North Am. 2011;40:591–614.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. de Jong FH, et al. Peripheral hormone levels in controls and patients with prostatic cancer or benign prostatic hyperplasia: results from the Dutch-Japanese case-control study. Cancer Res. 1991;51:3445–50.

    PubMed  Google Scholar 

  40. Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of childhood and adult obesity in the United States, 2011-2012. JAMA. 2014;311:806–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Cohen PG. Obesity in men: the hypogonadal-estrogen receptor relationship and its effect on glucose homeostasis. Med Hypotheses. 2008;70:358–60.

    CAS  PubMed  Google Scholar 

  42. Schneider G, Kirschner MA, Berkowitz R, Ertel NH. Increased estrogen production in obese men. J Clin Endocrinol Metab. 1979;48:633–8.

    CAS  PubMed  Google Scholar 

  43. Leitner L., et al. Osteopontin promotes aromatase expression and estradiol production in human adipocytes. Breast Cancer Res Treat. 2015;154:63–9.

    CAS  PubMed  Google Scholar 

  44. Williams G. Aromatase up-regulation, insulin and raised intracellular oestrogens in men, induce adiposity, metabolic syndrome and prostate disease, via aberrant ER-alpha and GPER signalling. Mol Cell Endocrinol. 2012;351:269–78.

    CAS  PubMed  Google Scholar 

  45. Prins GS. Endocrine disruptors and prostate cancer risk. Endocr Relat Cancer. 2008;15:649–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Keum N., et al. Adult weight gain and adiposity-related cancers: a dose-response meta-analysis of prospective observational studies. J Natl Cancer Inst. 2015;107:1–14.

  47. Di Zazzo E, Galasso G, Giovannelli P, Di Donato M, Castoria G. Estrogens and their receptors in prostate cancer: therapeutic implications. Front Oncol. 2018;8:2.

    PubMed  PubMed Central  Google Scholar 

  48. Goris Gbenou MC, Peltier A, Schulman CC, Velthoven RV. Increased body mass index as a risk factor in localized prostate cancer treated by radical prostatectomy. Urol Oncol. 2016;34:254.e1–6.

    Google Scholar 

  49. Gross M, et al. Expression of androgen and estrogen related proteins in normal weight and obese prostate cancer patients. Prostate. 2009;69:520–7.

    CAS  PubMed  Google Scholar 

  50. Laukkanen JA, et al. Metabolic syndrome and the risk of prostate cancer in Finnish men: a population-based study. Cancer Epidemiol Biomark Prev. 2004;13:1646–50.

    CAS  Google Scholar 

  51. Hammarsten J, Hogstedt B. Clinical haemodynamic, anthropometric, metabolic and insulin profile of men with high-stage and high-grade clinical prostate cancer. Blood Press. 2004;13:47–55.

    CAS  PubMed  Google Scholar 

  52. Dimitropoulou P, et al. Association of obesity with prostate cancer: a case-control study within the population-based PSA testing phase of the ProtecT study. Br J Cancer. 2011;104:875–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Rundle A, Richards C, Neugut AI. Body composition, abdominal fat distribution, and prostate-specific antigen test results. Cancer Epidemiol Biomark Prev. 2009;18:331–6.

    CAS  Google Scholar 

  54. Freedland SJ, Platz EA. Obesity and prostate cancer: making sense out of apparently conflicting data. Epidemiol Rev. 2007;29:88–97.

    PubMed  Google Scholar 

  55. Rhee H, Vela I, Chung E. Metabolic syndrome and prostate cancer: a review of complex interplay amongst various endocrine factors in the pathophysiology and progression of prostate cancer. Horm Cancer. 2016;7:75–83.

    PubMed  Google Scholar 

  56. Huggins C, Hodges CV. Studies on prostatic cancer: I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. 1941. J Urol. 2002;168:9–12.

    PubMed  Google Scholar 

  57. Sciarra A, et al. Oral ethinylestradiol in castration-resistant prostate cancer: a 10-year experience. Int J Urol. 2015;22:98–103.

    CAS  PubMed  Google Scholar 

  58. Mohler JL, et al. Prostate cancer, version 2.2014. J Natl Compr Cancer Netw. 2014;12:686–718.

    CAS  Google Scholar 

  59. Heidenreich A, et al. EAU guidelines on prostate cancer. Part II: Treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur Urol. 2014;65:467–79.

    CAS  PubMed  Google Scholar 

  60. Hedlund PO, et al. Parenteral estrogen versus combined androgen deprivation in the treatment of metastatic prostatic cancer: part 2. Final evaluation of the Scandinavian Prostatic Cancer Group (SPCG) Study No. 5. Scand J Urol Nephrol. 2008;42:220–9.

    CAS  PubMed  Google Scholar 

  61. Langley RE, et al. Cardiovascular outcomes in patients with locally advanced and metastatic prostate cancer treated with luteinising-hormone-releasing-hormone agonists or transdermal oestrogen: the randomised, phase 2 MRC PATCH trial (PR09). Lancet Oncol. 2013;14:306–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Mikkola A, Aro J, Rannikko S, Oksanen H, Ruutu M. Finnprostate g. Cardiovascular complications in patients with advanced prostatic cancer treated by means of orchiectomy or polyestradiol phosphate. Scand J Urol Nephrol. 2005;39:294–300.

    CAS  PubMed  Google Scholar 

  63. Ockrim JL, et al. Transdermal estradiol improves bone density when used as single agent therapy for prostate cancer. J Urol. 2004;172:2203–7.

    CAS  PubMed  Google Scholar 

  64. Norman G, et al. Parenteral oestrogen in the treatment of prostate cancer: a systematic review. Br J Cancer. 2008;98:697–707.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Turo R, et al. Diethylstilboestrol for the treatment of prostate cancer: past, present and future. Scand J Urol. 2014;48:4–14.

    CAS  PubMed  Google Scholar 

  66. Geier R, Adler S, Rashid G, Klein A. The synthetic estrogen diethylstilbestrol (DES) inhibits the telomerase activity and gene expression of prostate cancer cells. Prostate. 2010;70:1307–12.

    CAS  PubMed  Google Scholar 

  67. Koong LY, Watson CS. Direct estradiol and diethylstilbestrol actions on early- versus late-stage prostate cancer cells. Prostate. 2014;74:1589–603.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Montgomery B, et al. Estradiol suppresses tissue androgens and prostate cancer growth in castration resistant prostate cancer. Bmc Cancer. 2010;10:244.

    PubMed  PubMed Central  Google Scholar 

  69. Izumi K, et al. Ethinylestradiol improves prostate-specific antigen levels in pretreated castration-resistant prostate cancer patients. Anticancer Res. 2010;30:5201–5.

    CAS  PubMed  Google Scholar 

  70. Clemons J, Glode LM, Gao D, Flaig TW. Low-dose diethylstilbestrol for the treatment of advanced prostate cancer. Urol Oncol. 2013;31:198–204.

    CAS  PubMed  Google Scholar 

  71. Serrate C, et al. Diethylstilbestrol (DES) retains activity and is a reasonable option in patients previously treated with docetaxel for castration-resistant prostate cancer. Ann Oncol. 2009;20:965.

    CAS  PubMed  Google Scholar 

  72. Wilkins A, et al. Diethylstilbestrol in castration-resistant prostate cancer. BJU Int. 2012;110:E727–735.

    CAS  PubMed  Google Scholar 

  73. von Schoultz B, et al. Estrogen therapy and liver function—metabolic effects of oral and parenteral administration. Prostate. 1989;14:389–95.

    Google Scholar 

  74. Shamash J, et al. A multi-centre randomised phase III trial of dexamethasone vs dexamethasone and diethylstilbestrol in castration-resistant prostate cancer: immediate vs deferred diethylstilbestrol. Br J Cancer. 2011;104:620–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Ockrim J, Lalani el N, Abel P. Therapy insight: parenteral estrogen treatment for prostate cancer—a new dawn for an old therapy. Nat Clin Pract Oncol. 2006;3:552–63.

    CAS  PubMed  Google Scholar 

  76. Ricke WA, et al. Prostatic hormonal carcinogenesis is mediated by in situ estrogen production and estrogen receptor alpha signaling. FASEB J. 2008;22:1512–20.

    CAS  PubMed  Google Scholar 

  77. Price D, et al. Toremifene for the prevention of prostate cancer in men with high grade prostatic intraepithelial neoplasia: results of a double-blind, placebo controlled, phase IIB clinical trial. J Urol. 2006;176:965–70.

    CAS  PubMed  Google Scholar 

  78. Taneja SS, et al. Prostate cancer diagnosis among men with isolated high-grade intraepithelial neoplasia enrolled onto a 3-year prospective phase III clinical trial of oral toremifene. J Clin Oncol. 2013;31:523–9.

    CAS  PubMed  Google Scholar 

  79. Kim IY, et al. Raloxifene, a mixed estrogen agonist/antagonist, induces apoptosis in androgen-independent human prostate cancer cell lines. Cancer Res. 2002;62:5365–9.

    CAS  PubMed  Google Scholar 

  80. Shazer RL, et al. Raloxifene, an oestrogen-receptor-beta-targeted therapy, inhibits androgen-independent prostate cancer growth: results from preclinical studies and a pilot phase II clinical trial. BJU Int. 2006;97:691–7.

    CAS  PubMed  Google Scholar 

  81. Fujimura T, et al. Toremifene, a selective estrogen receptor modulator, significantly improved biochemical recurrence in bone metastatic prostate cancer: a randomized controlled phase II a trial. BMC Cancer. 2015;15:836.

    PubMed  PubMed Central  Google Scholar 

  82. Chadha MK, et al. Phase II study of fulvestrant (Faslodex) in castration resistant prostate cancer. Prostate. 2008;68:1461–6.

    CAS  PubMed  Google Scholar 

  83. Zhou JR, et al. Soybean phytochemicals inhibit the growth of transplantable human prostate carcinoma and tumor angiogenesis in mice. J Nutr. 1999;129:1628–35.

    CAS  PubMed  Google Scholar 

  84. Jacobsen BK, Knutsen SF, Fraser GE. Does high soy milk intake reduce prostate cancer incidence? The Adventist Health Study (United States). Cancer Causes Control. 1998;9:553–7.

    CAS  PubMed  Google Scholar 

  85. Ozasa K, et al. Serum phytoestrogens and prostate cancer risk in a nested case-control study among Japanese men. Cancer Sci. 2004;95:65–71.

    CAS  PubMed  Google Scholar 

  86. Vardi A, et al. Soy phytoestrogens modify DNA methylation of GSTP1, RASSF1A, EPH2 and BRCA1 promoter in prostate cancer cells. Vivo. 2010;24:393–400.

    CAS  Google Scholar 

  87. Hedelin M, et al. Dietary phytoestrogen, serum enterolactone and risk of prostate cancer: the cancer prostate Sweden study (Sweden). Cancer Causes Control. 2006;17:169–80.

    PubMed  Google Scholar 

  88. Dalais FS, et al. Effects of a diet rich in phytoestrogens on prostate-specific antigen and sex hormones in men diagnosed with prostate cancer. Urology. 2004;64:510–5.

    PubMed  Google Scholar 

  89. Thelen P, Wuttke W, Seidlova-Wuttke D. Phytoestrogens selective for the estrogen receptor beta exert anti-androgenic effects in castration resistant prostate cancer. J Steroid Biochem Mol Biol. 2014;139:290–3.

    CAS  PubMed  Google Scholar 

  90. Prins GS, Korach KS. The role of estrogens and estrogen receptors in normal prostate growth and disease. Steroids. 2008;73:233–44.

    CAS  PubMed  Google Scholar 

  91. Pisolato R., et al Expression and regulation of the estrogen receptors in PC-3 human prostate cancer cells. Steroids. 2016;107:74–86.

    CAS  PubMed  Google Scholar 

  92. Clinicaltrials.gov. U.S. National Library of Medicine. https://clinicaltrials.gov/. Accessed 14 May 2018.

  93. Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson JA. Cloning of a novel receptor expressed in rat prostate and ovary. Proc Natl Acad Sci USA. 1996;93:5925–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Nakayama T, et al. Epigenetic regulation of androgen receptor gene expression in human prostate cancers. Lab Investig. 2000;80:1789–96.

    CAS  PubMed  Google Scholar 

  95. Lin J, et al. Disulfiram is a DNA demethylating agent and inhibits prostate cancer cell growth. Prostate. 2011;71:333–43.

    CAS  PubMed  Google Scholar 

  96. Sharma V, et al. Disulfiram and its novel derivative sensitize prostate cancer cells to the growth regulatory mechanisms of the cell by re-expressing the epigenetically repressed tumor suppressor-estrogen receptor beta. Mol Carcinog. 2015;55:1843–57.

    PubMed  Google Scholar 

  97. Ittmann M, et al. Animal models of human prostate cancer: the consensus report of the New York meeting of the Mouse Models of Human Cancers Consortium Prostate Pathology Committee. Cancer Res. 2013;73:2718–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Hu WY, Shi GB, Hu DP, Nelles JL, Prins GS. Actions of estrogens and endocrine disrupting chemicals on human prostate stem/progenitor cells and prostate cancer risk. Mol Cell Endocrinol. 2012;354:63–73.

    CAS  PubMed  Google Scholar 

  99. Hu WY, et al. Isolation and functional interrogation of adult human prostate epithelial stem cells at single cell resolution. Stem Cell Res. 2017;23:1–12.

    PubMed  PubMed Central  Google Scholar 

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Correspondence to Michael R. Abern.

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Dobbs, R.W., Malhotra, N.R., Greenwald, D.T. et al. Estrogens and prostate cancer. Prostate Cancer Prostatic Dis 22, 185–194 (2019). https://doi.org/10.1038/s41391-018-0081-6

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