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Hormonal Carcinogenesis: The Role of Estrogens

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Abstract

This chapter focuses on the role of estrogens and their roles in cancer with an emphasis on prostate biology. It is now apparent that estrogens, both those synthesized by the body and those from our environment, target estrogen-responsive tissues at all stages of development and maturation. Little is known about the mechanisms involved in estrogen stimulation of carcinogenesis and less is known about how to prevent or treat cancer through estrogenic pathways. To better understand how estrogens mediate their carcinogenic effects, the respective roles of estrogen receptor alpha (ER-α) and estrogen receptor beta (ER-β) must be elucidated in the epithelial and stromal cells that constitute each tissue. Lastly, the significance of estrogen receptor (ER) signaling during various ontogenic periods must be determined. Answers to these questions will further our understanding of the mechanisms of estrogen/ER signaling and will serve as a basis for chemo-preventive and/or chemo-therapeutic strategies for estrogen-induced cancers.

Keywords

  • Estrogen
  • Prostate
  • Stromal-epithelial interactions
  • Breast
  • Paracrine

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Fig. 20.1
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References

  1. Belanger A, Candas B, Dupont A, et al. Changes in serum concentrations of conjugated and unconjugated steroids in 40- to 80-year-old men. J Clin Endocrinol Metab. 1994;79:1086–90.

    CAS  PubMed  Google Scholar 

  2. de Jong FH, Oishi K, Hayes RB, 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 

  3. Ellis L, Nyborg H. Racial/ethnic variations in male testosterone levels: a probable contributor to group differences in health. Steroids. 1992;57:72–5.

    CAS  PubMed  CrossRef  Google Scholar 

  4. Wu AH, Whittemore AS, Kolonel LN, et al. Serum androgens and sex hormone-binding globulins in relation to lifestyle factors in older African-American, white, and Asian men in the United States and Canada. Cancer Epidemiol Biomarkers Prev. 1995;4:735–41.

    CAS  PubMed  Google Scholar 

  5. Ellem SJ, Risbridger GP. Aromatase and prostate cancer. Minerva Endocrinol. 2006;31:1–12.

    CAS  PubMed  Google Scholar 

  6. Ellem SJ, Schmitt JF, Pedersen JS, Frydenberg M, Risbridger GP. Local aromatase expression in human prostate is altered in malignancy. J Clin Endocrinol Metab. 2004;89:2434–41.

    CAS  PubMed  CrossRef  Google Scholar 

  7. Ricke WA, McPherson SJ, Bianco JJ, 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  CrossRef  Google Scholar 

  8. Russo J, Hasan Lareef M, Balogh G, Guo S, Russo IH. Estrogen and its metabolites are carcinogenic agents in human breast epithelial cells. J Steroid Biochem Mol Biol. 2003;87:1–25.

    CAS  PubMed  CrossRef  Google Scholar 

  9. Carruba G. Estrogens and mechanisms of prostate cancer progression. Ann N Y Acad Sci. 2006;1089:201–17.

    CAS  PubMed  CrossRef  Google Scholar 

  10. Vermeulen A, Kaufman JM, Goemaere S, van Pottelberg I. Estradiol in elderly men. Aging Male. 2002;5:98–102.

    CAS  PubMed  CrossRef  Google Scholar 

  11. Cunha GR, Ricke W, Thomson A, et al. Hormonal, cellular, and molecular regulation of normal and neoplastic prostatic development. J Steroid Biochem Mol Biol. 2004;92:221–36.

    CAS  PubMed  CrossRef  Google Scholar 

  12. Risbridger G, Wang H, Frydenberg M, Cunha GR. The metaplastic effects of estrogen on prostate epithelium: proliferation of cells with basal cell phenotype. Endocrinology. 2001;142:2443–50.

    CAS  PubMed  Google Scholar 

  13. Martikainen P, Harkonen P, Vanhala T, et al. Multihormonal control of synthesis and secretion of prostatein in cultured rat ventral prostate. Endocrinology. 1987;121:604–11.

    CAS  PubMed  CrossRef  Google Scholar 

  14. Nevalainen MT, Harkonen PL, Valve EM, et al. Hormone regulation of human prostate in organ culture. Cancer Res. 1993;53:5199–207.

    CAS  PubMed  Google Scholar 

  15. Nevalainen MT, Valve EM, Makela SI, et al. Estrogen and prolactin regulation of rat dorsal and lateral prostate in organ culture. Endocrinology. 1991;129:612–22.

    CAS  PubMed  CrossRef  Google Scholar 

  16. Gennigens C, Menetrier-Caux C, Droz JP. Insulin-like growth factor (IGF) family and prostate cancer. Crit Rev Oncol Hematol. 2006;58:124–45.

    CAS  PubMed  CrossRef  Google Scholar 

  17. Hurle RA, Davies G, Parr C, et al. Hepatocyte growth factor/scatter factor and prostate cancer: a review. Histol Histopathol. 2005;20:1339–49.

    CAS  PubMed  Google Scholar 

  18. Zhu B, Kyprianou N. Transforming growth factor beta and prostate cancer. Cancer Treat Res. 2005;126:157–73.

    PubMed  CrossRef  Google Scholar 

  19. Djakiew D. Role of nerve growth factor-like protein in the paracrine regulation of prostate growth. J Androl. 1992;13:476–87.

    CAS  PubMed  Google Scholar 

  20. Dow JK, deVere White RW. Fibroblast growth factor 2: its structure and property, paracrine function, tumor angiogenesis, and prostate-related mitogenic and oncogenic functions. Urology. 2000;55:800–6.

    CAS  PubMed  CrossRef  Google Scholar 

  21. Levin ER. Extranuclear estrogen receptor’s roles in physiology: lessons from mouse models. Am J Physiol Endocrinol Metabol. 2014;307:E133–40.

    CAS  CrossRef  Google Scholar 

  22. Nicholson TM, Ricke WA. Androgens and estrogens in benign prostatic hyperplasia: past, present and future. Differentiation. 2011;82:184–99.

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  23. Nilsson S, Makela S, Treuter E, et al. Mechanisms of estrogen action. Physiol Rev. 2001;81:1535–65.

    CAS  PubMed  Google Scholar 

  24. Couse JF, Korach KS. Estrogen receptor null mice: what have we learned and where will they lead us? Endocr Rev. 1999;20:358–417.

    CAS  PubMed  CrossRef  Google Scholar 

  25. 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 U S A. 1996;93:5925–30.

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  26. Nicholson TM, Sehgal PD, Drew SA, Huang W, Ricke WA. Sex steroid receptor expression and localization in benign prostatic hyperplasia varies with tissue compartment. Differentiation. 2013;85:140–9.

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  27. Prossnitz ER, Barton M. The G-protein-coupled estrogen receptor GPER in health and disease. Nat Rev Endocrinol. 2011;7:715–26.

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  28. Lappano R, De Marco P, De Francesco EM, et al. Cross-talk between GPER and growth factor signaling. J Steroid Biochem Mol Biol. 2013;137:50–6.

    CAS  PubMed  CrossRef  Google Scholar 

  29. Barton M. Position paper: the membrane estrogen receptor GPER--Clues and questions. Steroids. 2012;77:935–42.

    CAS  PubMed  CrossRef  Google Scholar 

  30. Pedram A, Razandi M, Lewis M, Hammes S, Levin ER. Membrane-localized estrogen receptor alpha is required for normal organ development and function. Dev Cell. 2014;29:482–90.

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  31. Cavalieri E, Frenkel K, Liehr JG, Rogan E, Roy D. Estrogens as endogenous genotoxic agents—DNA adducts and mutations. J Natl Cancer Inst Monogr. 2000;27:75–93.

    CAS  CrossRef  Google Scholar 

  32. Liehr JG, Ballatore AM, McLachlan JA, Sirbasku DA. Mechanism of diethylstilbestrol carcinogenicity as studied with the fluorinated analogue E-3′,3″,5′,5″-tetrafluorodiethylstilbestrol. Cancer Res. 1983;43:2678–82.

    CAS  PubMed  Google Scholar 

  33. Aoyama T, Korzekwa K, Nagata K, et al. Estradiol metabolism by complementary deoxyribonucleic acid-expressed human cytochrome P450s. Endocrinology. 1990;126:3101–6.

    CAS  PubMed  CrossRef  Google Scholar 

  34. Guengerich FP. Characterization of human microsomal cytochrome P-450 enzymes. Annu Rev Pharmacol Toxicol. 1989;29:241–64.

    CAS  PubMed  CrossRef  Google Scholar 

  35. Hammond DK, Zhu BT, Wang MY, Ricci MJ, Liehr JG. Cytochrome P450 metabolism of estradiol in hamster liver and kidney. Toxicol Appl Pharmacol. 1997;145:54–60.

    CAS  PubMed  CrossRef  Google Scholar 

  36. Kerlan V, Dreano Y, Bercovici JP, et al. Nature of cytochromes P450 involved in the 2-/4-hydroxylations of estradiol in human liver microsomes. Biochem Pharmacol. 1992;44:1745–56.

    CAS  PubMed  CrossRef  Google Scholar 

  37. Weisz J, Bui QD, Roy D, Liehr JG. Elevated 4-hydroxylation of estradiol by hamster kidney microsomes: a potential pathway of metabolic activation of estrogens. Endocrinology. 1992;131:655–61.

    CAS  PubMed  Google Scholar 

  38. Bui Q, Weisz J. Identification of microsomal, organic hydroperoxide-dependent catechol estrogen formation: comparison with NADPH-dependent mechanism. Pharmacology. 1988;36:356–64.

    CAS  PubMed  CrossRef  Google Scholar 

  39. Paria BC, Chakraborty C, Dey SK. Catechol estrogen formation in the mouse uterus and its role in implantation. Mol Cell Endocrinol. 1990;69:25–32.

    CAS  PubMed  CrossRef  Google Scholar 

  40. Hayes CL, Spink DC, Spink BC, et al. 17 Beta-estradiol hydroxylation catalyzed by human cytochrome P450 1B1. Proc Natl Acad Sci U S A. 1996;93:9776–81.

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  41. Sutter TR, Tang YM, Hayes CL, et al. Complete cDNA sequence of a human dioxin-inducible mRNA identifies a new gene subfamily of cytochrome P450 that maps to chromosome 2. J Biol Chem. 1994;269:13092–9.

    CAS  PubMed  Google Scholar 

  42. Zhu BT, Conney AH. Functional role of estrogen metabolism in target cells: review and perspectives. Carcinogenesis. 1998;19:1–27.

    PubMed  CrossRef  Google Scholar 

  43. Palmer JR, Rosenberg L, Kaufman DW, et al. Oral contraceptive use and liver cancer. Am J Epidemiol. 1989;130:878–82.

    CAS  PubMed  Google Scholar 

  44. Lavigne JA, Helzlsouer KJ, Huang HY, et al. An association between the allele coding for a low activity variant of catechol-O-methyltransferase and the risk for breast cancer. Cancer Res. 1997;57:5493–7.

    CAS  PubMed  Google Scholar 

  45. Cavalieri E, Chakravarti D, Guttenplan J, et al. Catechol estrogen quinones as initiators of breast and other human cancers: implications for biomarkers of susceptibility and cancer prevention. Biochim Biophys Acta. 2006;1766:63–78.

    CAS  PubMed  Google Scholar 

  46. Cavalieri EL, Devanesan P, Bosland MC, Badawi AF, Rogan EG. Catechol estrogen metabolites and conjugates in different regions of the prostate of Noble rats treated with 4-hydroxyestradiol: implications for estrogen-induced initiation of prostate cancer. Carcinogenesis. 2002;23:329–33.

    CAS  PubMed  CrossRef  Google Scholar 

  47. Russo J, Lareef MH, Tahin Q, et al. 17Beta-estradiol is carcinogenic in human breast epithelial cells. J Steroid Biochem Mol Biol. 2002;80:149–62.

    CAS  PubMed  CrossRef  Google Scholar 

  48. Tsutsui T, Tamura Y, Suzuki A, et al. Mammalian cell transformation and aneuploidy induced by five bisphenols. Int J Cancer. 2000;86:151–4.

    CAS  PubMed  CrossRef  Google Scholar 

  49. Tsutsui T, Tamura Y, Yagi E, Barrett JC. Involvement of genotoxic effects in the initiation of estrogen-induced cellular transformation: studies using Syrian hamster embryo cells treated with 17beta-estradiol and eight of its metabolites. Int J Cancer. 2000;86:8–14.

    CAS  PubMed  CrossRef  Google Scholar 

  50. Cavalieri EL, Stack DE, Devanesan PD, et al. Molecular origin of cancer: catechol estrogen-3,4-quinones as endogenous tumor initiators. Proc Natl Acad Sci U S A. 1997;94:10937–42.

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  51. Li KM, Todorovic R, Devanesan P, et al. Metabolism and DNA binding studies of 4-hydroxyestradiol and estradiol-3,4-quinone in vitro and in female ACI rat mammary gland in vivo. Carcinogenesis. 2004;25:289–97.

    CAS  PubMed  CrossRef  Google Scholar 

  52. Liehr JG. Hormone-associated cancer: mechanistic similarities between human breast cancer and estrogen-induced kidney carcinogenesis in hamsters. Environ Health Perspect. 1997;105:565–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Liehr JG. Dual role of oestrogens as hormones and pro-carcinogens: tumour initiation by metabolic activation of oestrogens. Eur J Cancer Prev. 1997;6:3–10.

    CAS  PubMed  CrossRef  Google Scholar 

  54. Liehr JG. Role of DNA adducts in hormonal carcinogenesis. Regul Toxicol Pharmacol. 2000;32:276–82.

    CAS  PubMed  CrossRef  Google Scholar 

  55. Liehr JG. Genotoxicity of the steroidal oestrogens oestrone and oestradiol: possible mechanism of uterine and mammary cancer development. Hum Reprod Update. 2001;7:273–81.

    CAS  PubMed  CrossRef  Google Scholar 

  56. Mailander PC, Meza JL, Higginbotham S, Chakravarti D. Induction of A.T to G.C mutations by erroneous repair of depurinated DNA following estrogen treatment of the mammary gland of ACI rats. J Steroid Biochem Mol Biol. 2006;101:204–15.

    CAS  PubMed  CrossRef  Google Scholar 

  57. Markushin Y, Zhong W, Cavalieri EL, et al. Spectral characterization of catechol estrogen quinone (CEQ)-derived DNA adducts and their identification in human breast tissue extract. Chem Res Toxicol. 2003;16:1107–17.

    CAS  PubMed  CrossRef  Google Scholar 

  58. Melendez-Colon VJ, Smith CA, Seidel A, et al. Formation of stable adducts and absence of depurinating DNA adducts in cells and DNA treated with the potent carcinogen dibenzo[a, l]pyrene or its diol epoxides. Proc Natl Acad Sci U S A. 1997;94:13542–7.

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  59. Zhao Z, Kosinska W, Khmelnitsky M, et al. Mutagenic activity of 4-hydroxyestradiol, but not 2-hydroxyestradiol, in BB rat2 embryonic cells, and the mutational spectrum of 4-hydroxyestradiol. Chem Res Toxicol. 2006;19:475–9.

    CAS  PubMed  CrossRef  Google Scholar 

  60. Yuan F, Chen DZ, Liu K, et al. Anti-estrogenic activities of indole-3-carbinol in cervical cells: implication for prevention of cervical cancer. Anticancer Res. 1999;19:1673–80.

    CAS  PubMed  Google Scholar 

  61. Delvenne P, Herman L, Kholod N, et al. Role of hormone cofactors in the human papillomavirus-induced carcinogenesis of the uterine cervix. Mol Cell Endocrinol. 2007;264:1–5.

    CAS  PubMed  CrossRef  Google Scholar 

  62. Muti P, Westerlind K, Wu T, et al. Urinary estrogen metabolites and prostate cancer: a case-control study in the United States. Cancer Causes Control. 2002;13:947–55.

    PubMed  CrossRef  Google Scholar 

  63. Newbold RR, Liehr JG. Induction of uterine adenocarcinoma in CD-1 mice by catechol estrogens. Cancer Res. 2000;60:235–7.

    CAS  PubMed  Google Scholar 

  64. Barrett JC, Wong A, McLachlan JA. Diethylstilbestrol induces neoplastic transformation without measurable gene mutation at two loci. Science. 1981;212:1402–4.

    CAS  PubMed  CrossRef  Google Scholar 

  65. Tsutsui T, Barrett JC. Neoplastic transformation of cultured mammalian cells by estrogens and estrogenlike chemicals. Environ Health Perspect. 1997;105:619–24.

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  66. Tsutsui T, Suzuki N, Fukuda S, et al. 17Beta-estradiol-induced cell transformation and aneuploidy of Syrian hamster embryo cells in culture. Carcinogenesis. 1987;8:1715–9.

    CAS  PubMed  CrossRef  Google Scholar 

  67. Aizu-Yokota E, Ichinoseki K, Sato Y. Microtubule disruption induced by estradiol in estrogen receptor-positive and -negative human breast cancer cell lines. Carcinogenesis. 1994;15:1875–9.

    CAS  PubMed  CrossRef  Google Scholar 

  68. Aizu-Yokota E, Susaki A, Sato Y. Natural estrogens induce modulation of microtubules in Chinese hamster V79 cells in culture. Cancer Res. 1995;55:1863–8.

    CAS  PubMed  Google Scholar 

  69. Epe B, Hegler J, Metzler M. Site-specific covalent binding of stilbene-type and steroidal estrogens to tubulin following metabolic activation in vitro. Carcinogenesis. 1987;8:1271–5.

    CAS  PubMed  CrossRef  Google Scholar 

  70. Sakakibara Y, Saito I, Ichinoseki K, et al. Effects of diethylstilbestrol and its methyl ethers on aneuploidy induction and microtubule distribution in Chinese hamster V79 cells. Mutat Res. 1991;263:269–76.

    CAS  PubMed  CrossRef  Google Scholar 

  71. Tucker RW, Barrett JC. Deceased numbers of spindle and cytoplasmic microtubules in hamster embryo cells treated with a carcinogen, diethylstilbestrol. Cancer Res. 1986;46:2088–95.

    CAS  PubMed  Google Scholar 

  72. Endo S, Metzler M, Hieber L. Nonrandom karyotypic changes in a spontaneously immortalized and tumourigenic Syrian hamster embryo cell line. Carcinogenesis. 1994;15:2387–90.

    CAS  PubMed  CrossRef  Google Scholar 

  73. Lengauer C, Kinzler KW, Vogelstein B. Genetic instabilities in human cancers. Nature. 1998;396:643–9.

    CAS  PubMed  CrossRef  Google Scholar 

  74. Schmuck G, Lieb G, Wild D, Schiffmann D, Henschler D. Characterization of an in vitro micronucleus assay with Syrian hamster embryo fibroblasts. Mutat Res. 1988;203:397–404.

    CAS  PubMed  CrossRef  Google Scholar 

  75. Cavalieri EL, Rogan EG. A unified mechanism in the initiation of cancer. Ann N Y Acad Sci. 2002;959:341–54.

    CAS  PubMed  CrossRef  Google Scholar 

  76. Jefcoate CR, Liehr JG, Santen RJ, et al. Tissue-specific synthesis and oxidative metabolism of estrogens. J Natl Cancer Inst Monogr. 2000;27:95–112.

    CAS  CrossRef  Google Scholar 

  77. Kuiper GG, Carlsson B, Grandien K, et al. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology. 1997;138:863–70.

    CAS  PubMed  Google Scholar 

  78. Kuiper GG, Lemmen JG, Carlsson B, et al. Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta. Endocrinology. 1998;139:4252–63.

    CAS  PubMed  Google Scholar 

  79. Pendaries C, Darblade B, Rochaix P, et al. The AF-1 activation-function of ERalpha may be dispensable to mediate the effect of estradiol on endothelial NO production in mice. Proc Natl Acad Sci U S A. 2002;99:2205–10.

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  80. Leung YK, Mak P, Hassan S, Ho SM. Estrogen receptor (ER)-beta isoforms: a key to understanding ER-beta signaling. Proc Natl Acad Sci U S A. 2006;103:13162–7.

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  81. Omoto Y, Imamov O, Warner M, Gustafsson JA. Estrogen receptor alpha and imprinting of the neonatal mouse ventral prostate by estrogen. Proc Natl Acad Sci U S A. 2005;102:1484–9.

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  82. Couse JF, Korach KS. Estrogen receptor-alpha mediates the detrimental effects of neonatal diethylstilbestrol (DES) exposure in the murine reproductive tract. Toxicology. 2004;205:55–63.

    CAS  PubMed  CrossRef  Google Scholar 

  83. Nicholson TM, Moses MA, Uchtmann KS, et al. Estrogen receptor-alpha is a key mediator and therapeutic target for bladder complications of benign prostatic hyperplasia. J Urol. 2015;193:722–9.

    CAS  PubMed  CrossRef  Google Scholar 

  84. Imamov O, Morani A, Shim GJ, et al. Estrogen receptor beta regulates epithelial cellular differentiation in the mouse ventral prostate. Proc Natl Acad Sci U S A. 2004;101:9375–80.

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  85. Dupont S, Krust A, Gansmuller A, et al. Effect of single and compound knockouts of estrogen receptors alpha (ERalpha) and beta (ERbeta) on mouse reproductive phenotypes. Development. 2000;127:4277–91.

    CAS  PubMed  Google Scholar 

  86. Risbridger G, Wang H, Young P, et al. Evidence that epithelial and mesenchymal estrogen receptor-alpha mediates effects of estrogen on prostatic epithelium. Dev Biol. 2001;229:432–42.

    CAS  PubMed  CrossRef  Google Scholar 

  87. Cunha GR, Lung B. The importance of stroma in morphogenesis and functional activity of urogenital epithelium. In Vitro. 1979;15:50–71.

    CAS  PubMed  CrossRef  Google Scholar 

  88. Prins GS. Developmental estrogenization of the prostate gland. In: Naz RK, editor. Prostate: basic and clinical aspects. Boca Raton: CRC Press; 1997. p. 245–66.

    Google Scholar 

  89. Prins GS, Marmer M, Woodham C, et al. Estrogen receptor-beta messenger ribonucleic acid ontogeny in the prostate of normal and neonatally estrogenized rats. Endocrinology. 1998;139:874–83.

    CAS  PubMed  Google Scholar 

  90. Prins GS, Birch L, Couse JF, et al. Estrogen imprinting of the developing prostate gland is mediated through stromal estrogen receptor alpha: studies with alphaERKO and betaERKO mice. Cancer Res. 2001;61:6089–97.

    CAS  PubMed  Google Scholar 

  91. Weihua Z, Makela S, Andersson LC, et al. A role for estrogen receptor beta in the regulation of growth of the ventral prostate. Proc Natl Acad Sci U S A. 2001;98:6330–5.

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  92. Buchanan DL, Kurita T, Taylor JA, et al. Role of stromal and epithelial estrogen receptors in vaginal epithelial proliferation, stratification, and cornification. Endocrinology. 1998;139:4345–52.

    CAS  PubMed  Google Scholar 

  93. Chang WY, Birch L, Woodham C, Gold LI, Prins GS. Neonatal estrogen exposure alters the transforming growth factor-beta signaling system in the developing rat prostate and blocks the transient p21(cip1/waf1) expression associated with epithelial differentiation. Endocrinology. 1999;140:2801–13.

    CAS  PubMed  Google Scholar 

  94. Estrogens, steroidal. Rep Carcinog. 2002;10:116–9.

    Google Scholar 

  95. Berrino F, Muti P, Micheli A, et al. Serum sex hormone levels after menopause and subsequent breast cancer. J Natl Cancer Inst. 1996;88:291–6.

    CAS  PubMed  CrossRef  Google Scholar 

  96. van Landeghem AA, Poortman J, Nabuurs M, Thijssen JH. Endogenous concentration and subcellular distribution of estrogens in normal and malignant human breast tissue. Cancer Res. 1985;45:2900–6.

    PubMed  Google Scholar 

  97. van Landeghem AA, Poortman J, Nabuurs M, Thijssen JH. Endogenous concentration and subcellular distribution of androgens in normal and malignant human breast tissue. Cancer Res. 1985;45:2907–12.

    PubMed  Google Scholar 

  98. Hulka BS, Liu ET, Lininger RA. Steroid hormones and risk of breast cancer. Cancer. 1994;74:1111–24.

    CAS  PubMed  CrossRef  Google Scholar 

  99. Thomas DB. Do hormones cause breast cancer? Cancer. 1984;53:595–604.

    CAS  PubMed  CrossRef  Google Scholar 

  100. Coffey DS. Similarities of prostate and breast cancer: evolution, diet, and estrogens. Urology. 2001;57:31–8.

    CAS  PubMed  CrossRef  Google Scholar 

  101. Stoll BA. Western diet, early puberty, and breast cancer risk. Breast Cancer Res Treat. 1998;49:187–93.

    CAS  PubMed  CrossRef  Google Scholar 

  102. Schneider HP, Mueck AO, Kuhl H. IARC monographs program on carcinogenicity of combined hormonal contraceptives and menopausal therapy. Climacteric. 2005;8:311–6.

    CAS  PubMed  CrossRef  Google Scholar 

  103. Colditz GA, Egan KM, Stampfer MJ. Hormone replacement therapy and risk of breast cancer: results from epidemiologic studies. Am J Obstet Gynecol. 1993;168:1473–80.

    CAS  PubMed  CrossRef  Google Scholar 

  104. Kelsey JL. Breast cancer epidemiology: summary and future directions. Epidemiol Rev. 1993;15:256–63.

    CAS  PubMed  Google Scholar 

  105. da Costa GG, McDaniel-Hamilton LP, Heflich RH, Marques MM, Beland FA. DNA adduct formation and mutant induction in Sprague-Dawley rats treated with tamoxifen and its derivatives. Carcinogenesis. 2001;22:1307–15.

    CrossRef  Google Scholar 

  106. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst. 1998;90:1371–88.

    CAS  PubMed  CrossRef  Google Scholar 

  107. Li JJ, Li SA. Causation and prevention of solely estrogen-induced oncogenesis: similarities to human ductal breast cancer. Adv Exp Med Biol. 2003;532:195–207.

    CAS  PubMed  CrossRef  Google Scholar 

  108. Li SA, Weroha SJ, Tawfik O, Li JJ. Prevention of solely estrogen-induced mammary tumors in female aci rats by tamoxifen: evidence for estrogen receptor mediation. J Endocrinol. 2002;175:297–305.

    CAS  PubMed  CrossRef  Google Scholar 

  109. Yang X, Edgerton SM, Kosanke SD, et al. Hormonal and dietary modulation of mammary carcinogenesis in mouse mammary tumor virus-c-erbB-2 transgenic mice. Cancer Res. 2003;63:2425–33.

    CAS  PubMed  Google Scholar 

  110. Yoshida M, Kudoh K, Katsuda S, et al. Inhibitory effects of uterine endometrial carcinogenesis in Donryu rats by tamoxifen. Cancer Lett. 1998;134:43–51.

    CAS  PubMed  CrossRef  Google Scholar 

  111. Liehr JG, Sirbasku DA, Jurka E, Randerath K, Randerath E. Inhibition of estrogen-induced renal carcinogenesis in male Syrian hamsters by tamoxifen without decrease in DNA adduct levels. Cancer Res. 1988;48:779–83.

    CAS  PubMed  Google Scholar 

  112. Yu FL, Bender W. A proposed mechanism of tamoxifen in breast cancer prevention. Cancer Detect Prev. 2002;26:370–5.

    CAS  PubMed  CrossRef  Google Scholar 

  113. Tryndyak VP, Kovalchuk O, Muskhelishvili L, et al. Epigenetic reprogramming of liver cells in tamoxifen-induced rat hepatocarcinogenesis. Mol Carcinog. 2007;46:187–97.

    CAS  PubMed  CrossRef  Google Scholar 

  114. Yager JD, Shi YE. Synthetic estrogens and tamoxifen as promoters of hepatocarcinogenesis. Prev Med. 1991;20:27–37.

    CAS  PubMed  CrossRef  Google Scholar 

  115. Tsutsui T, Taguchi S, Tanaka Y, Barrett JC. 17Beta-estradiol, diethylstilbestrol, tamoxifen, toremifene and ICI 164,384 induce morphological transformation and aneuploidy in cultured Syrian hamster embryo cells. Int J Cancer. 1997;70:188–93.

    CAS  PubMed  CrossRef  Google Scholar 

  116. Brendler CB, Berry SJ, Ewing LL, et al. Spontaneous benign prostatic hyperplasia in the beagle. Age-associated changes in serum hormone levels, and the morphology and secretory function of the canine prostate. J Clin Invest. 1983;71:1114–23.

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  117. Hayes RB, de Jong FH, Raatgever J, et al. Physical characteristics and factors related to sexual development and behaviour and the risk for prostatic cancer. Eur J Cancer Prev. 1992;1:239–45.

    CAS  PubMed  CrossRef  Google Scholar 

  118. Ross R, Bernstein L, Judd H, et al. Serum testosterone levels in healthy young black and white men. J Natl Cancer Inst. 1986;76:45–8.

    CAS  PubMed  Google Scholar 

  119. Noble RL. The development of prostatic adenocarcinoma in Nb rats following prolonged sex hormone administration. Cancer Res. 1977;37:1929–33.

    CAS  PubMed  Google Scholar 

  120. Ricke WA, Ishii K, Ricke EA, et al. Steroid hormones stimulate human prostate cancer progression and metastasis. Int J Cancer. 2006;118:2123–31.

    CAS  PubMed  CrossRef  Google Scholar 

  121. Wang Y, Hayward SW, Donjacour AA, et al. Sex hormone-induced carcinogenesis in Rb-deficient prostate tissue. Cancer Res. 2000;60:6008–17.

    CAS  PubMed  Google Scholar 

  122. Wang Y, Sudilovsky D, Zhang B, et al. A human prostatic epithelial model of hormonal carcinogenesis. Cancer Res. 2001;61:6064–72.

    CAS  PubMed  Google Scholar 

  123. Deslypere JP, Vermeulen A. Influence of age on steroid concentrations in skin and striated muscle in women and in cardiac muscle and lung tissue in men. J Clin Endocrinol Metab. 1985;61:648–53.

    CAS  PubMed  CrossRef  Google Scholar 

  124. Feldman HA, Longcope C, Derby CA, et al. Age trends in the level of serum testosterone and other hormones in middle-aged men: Longitudinal results from the Massachusetts male aging study. J Clin Endocrinol Metab. 2002;87:589–98.

    CAS  PubMed  CrossRef  Google Scholar 

  125. Gray A, Berlin JA, McKinlay JB, Longcope C. An examination of research design effects on the association of testosterone and male aging: results of a meta-analysis. J Clin Epidemiol. 1991;44:671–84.

    CAS  PubMed  CrossRef  Google Scholar 

  126. Griffiths K. Estrogens and prostatic disease. International Prostate Health Council Study Group. Prostate. 2000;45:87–100.

    CAS  PubMed  CrossRef  Google Scholar 

  127. Vermeulen A, Rubens R, Verdonck L. Testosterone secretion and metabolism in male senescence. J Clin Endocrinol Metab. 1972;34:730–5.

    CAS  PubMed  CrossRef  Google Scholar 

  128. Krieg M, Nass R, Tunn S. Effect of aging on endogenous level of 5 alpha-dihydrotestosterone, testosterone, estradiol, and estrone in epithelium and stroma of normal and hyperplastic human prostate. J Clin Endocrinol Metab. 1993;77:375–81.

    CAS  PubMed  Google Scholar 

  129. Ekbom A, Hsieh CC, Lipworth L, Adami HQ, Trichopoulos D. Intrauterine environment and breast cancer risk in women: a population-based study. J Natl Cancer Inst. 1997;89:71–6.

    CAS  PubMed  CrossRef  Google Scholar 

  130. Herbst AL, Cole P, Colton T, Robboy SJ, Scully RE. Age-incidence and risk of diethylstilbestrol-related clear cell adenocarcinoma of the vagina and cervix. Am J Obstet Gynecol. 1977;128:43–50.

    CAS  PubMed  CrossRef  Google Scholar 

  131. Herbst AL, Ulfelder H, Poskanzer DC. Adenocarcinoma of the vagina. Association of maternal stilbestrol therapy with tumor appearance in young women. N Engl J Med. 1971;284:878–81.

    CAS  PubMed  CrossRef  Google Scholar 

  132. Noller KL, Decker DG, Lanier AP, Kurland LT. Clear-cell adenocarcinoma of the cervix after maternal treatment with synthetic estrogens. Mayo Clin Proc. 1972;47:629–30.

    CAS  PubMed  Google Scholar 

  133. Robboy SJ, Scully RE, Welch WR, Herbst AL. Intrauterine diethylstilbestrol exposure and its consequences: pathologic characteristics of vaginal adenosis, clear cell adenocarcinoma, and related lesions. Arch Pathol Lab Med. 1977;101:1–5.

    CAS  PubMed  Google Scholar 

  134. Dorgan JF, Longcope C, Stephenson Jr HE, et al. Relation of prediagnostic serum estrogen and androgen levels to breast cancer risk. Cancer Epidemiol Biomarkers Prev. 1996;5:533–9.

    CAS  PubMed  Google Scholar 

  135. Secreto G, Toniolo P, Berrino F, et al. Serum and urinary androgens and risk of breast cancer in postmenopausal women. Cancer Res. 1991;51:2572–6.

    CAS  PubMed  Google Scholar 

  136. Thomas HV, Key TJ, Allen DS, et al. A prospective study of endogenous serum hormone concentrations and breast cancer risk in post-menopausal women on the island of Guernsey. Br J Cancer. 1997;76:401–5.

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  137. Zeleniuch-Jacquotte A, Bruning PF, Bonfrer JM, et al. Relation of serum levels of testosterone and dehydroepiandrosterone sulfate to risk of breast cancer in postmenopausal women. Am J Epidemiol. 1997;145:1030–8.

    CAS  PubMed  CrossRef  Google Scholar 

  138. Garland CF, Friedlander NJ, Barrett-Connor E, Khaw KT. Sex hormones and postmenopausal breast cancer: a prospective study in an adult community. Am J Epidemiol. 1992;135:1220–30.

    CAS  PubMed  Google Scholar 

  139. Wysowski DK, Comstock GW, Helsing KJ, Lau HL. Sex hormone levels in serum in relation to the development of breast cancer. Am J Epidemiol. 1987;125:791–9.

    CAS  PubMed  Google Scholar 

  140. James VH, McNeill JM, Lai LC, et al. Aromatase activity in normal breast and breast tumor tissues: in vivo and in vitro studies. Steroids. 1987;50:269–79.

    CAS  PubMed  CrossRef  Google Scholar 

  141. Thijssen JH, Blankenstein MA, Donker GH, Daroszewski J. Endogenous steroid hormones and local aromatase activity in the breast. J Steroid Biochem Mol Biol. 1991;39:799–804.

    CAS  PubMed  CrossRef  Google Scholar 

  142. Veronesi U, Pizzocaro G. Breast cancer in women subsequent to cystic disease of the breast. Surg Gynecol Obstet. 1968;126:529–32.

    CAS  PubMed  Google Scholar 

  143. Highman B, Greenman DL, Norvell MJ, Farmer J, Shellenberger TE. Neoplastic and preneoplastic lesions induced in female C3H mice by diets containing diethylstilbestrol or 17 beta-estradiol. J Environ Pathol Toxicol. 1980;4:81–95.

    CAS  PubMed  Google Scholar 

  144. Highman B, Roth SI, Greenman DL. Osseous changes and osteosacomas in mice continuously fed diets containing diethylstilbestrol or 17 beta-estradiol. J Natl Cancer Inst. 1981;67:653–62.

    CAS  PubMed  Google Scholar 

  145. Huseby RA. Demonstration of a direct carcinogenic effect of estradiol on Leydig cells of the mouse. Cancer Res. 1980;40:1006–13.

    CAS  PubMed  Google Scholar 

  146. Nagasawa H, Mori T, Nakajima Y. Long-term effects of progesterone or diethylstilbestrol with or without estrogen after maturity on mammary tumorigenesis in mice. Eur J Cancer. 1980;16:1583–9.

    CAS  PubMed  CrossRef  Google Scholar 

  147. Noble RL, Hochachka BC, King D. Spontaneous and estrogen-produced tumors in Nb rats and their behavior after transplantation. Cancer Res. 1975;35:766–80.

    CAS  PubMed  Google Scholar 

  148. Shull JD, Spady TJ, Snyder MC, Johansson SL, Pennington KL. Ovary-intact, but not ovariectomized female ACI rats treated with 17beta-estradiol rapidly develop mammary carcinoma. Carcinogenesis. 1997;18:1595–601.

    CAS  PubMed  CrossRef  Google Scholar 

  149. Cunha GR, Hayward SW, Wang YZ, Ricke WA. Role of the stromal microenvironment in carcinogenesis of the prostate. Int J Cancer. 2003;107:1–10.

    CAS  PubMed  CrossRef  Google Scholar 

  150. Leav I, Ho SM, Ofner P, et al. Biochemical alterations in sex hormone-induced hyperplasia and dysplasia of the dorsolateral prostates of Noble rats. J Natl Cancer Inst. 1988;80:1045–53.

    CAS  PubMed  CrossRef  Google Scholar 

  151. Noble RL. Prostate carcinoma of the Nb rat in relation to hormones. Int Rev Exp Pathol. 1982;23:113–59.

    CAS  PubMed  Google Scholar 

  152. McLachlan JA, Newbold RR, Bullock BC. Reproductive tract lesions in male mice exposed prenatally to diethylstilbestrol. Science. 1975;190:991–2.

    CAS  PubMed  CrossRef  Google Scholar 

  153. Prins GS. Neonatal estrogen exposure induces lobe-specific alterations in adult rat prostate androgen receptor expression. Endocrinology. 1992;130:3703–14.

    CAS  PubMed  CrossRef  Google Scholar 

  154. Prins GS, Huang L, Birch L, Pu Y. The role of estrogens in normal and abnormal development of the prostate gland. Ann N Y Acad Sci. 2006;1089:1–13.

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  155. 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  CrossRef  Google Scholar 

  156. Henderson BE, Bernstein L, Ross RK, Depue RH, Judd HL. The early in utero oestrogen and testosterone environment of blacks and whites: potential effects on male offspring. Br J Cancer. 1988;57:216–8.

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  157. Jemal A, Murray T, Ward E, et al. Cancer statistics, 2005. CA Cancer J Clin. 2005;55:10–30.

    PubMed  CrossRef  Google Scholar 

  158. Pylkkanen L, Santti R, Maentausta O, Vihko R. Distribution of estradiol-17 beta hydroxysteroid oxidoreductase in the urogenital tract of control and neonatally estrogenized male mice: immunohistochemical, enzymehistochemical, and biochemical study. Prostate. 1992;20:59–72.

    CAS  PubMed  CrossRef  Google Scholar 

  159. Pylkkanen L, Santti R, Newbold R, McLachlan JA. Regional differences in the prostate of the neonatally estrogenized mouse. Prostate. 1991;18:117–29.

    CAS  PubMed  CrossRef  Google Scholar 

  160. Arai Y, Mori T, Suzuki Y, Bern HA. Long-term effects of perinatal exposure to sex steroids and diethylstilbestrol on the reproductive system of male mammals. Int Rev Cytol. 1983;84:235–68.

    CAS  PubMed  CrossRef  Google Scholar 

  161. Strohsnitter WC, Noller KL, Hoover RN, et al. Cancer risk in men exposed in utero to diethylstilbestrol. J Natl Cancer Inst. 2001;93:545–51.

    CAS  PubMed  CrossRef  Google Scholar 

  162. Bosland MC, Ford H, Horton L. Induction at high incidence of ductal prostate adenocarcinomas in NBL/Cr and Sprague-Dawley Hsd:SD rats treated with a combination of testosterone and estradiol-17 beta or diethylstilbestrol. Carcinogenesis. 1995;16:1311–7.

    CAS  PubMed  CrossRef  Google Scholar 

  163. Drago JR. The induction of NB rat prostatic carcinomas. Anticancer Res. 1984;4:255–6.

    CAS  PubMed  Google Scholar 

  164. Leav I, Merk FB, Kwan PW, Ho SM. Androgen-supported estrogen-enhanced epithelial proliferation in the prostates of intact Noble rats. Prostate. 1989;15:23–40.

    CAS  PubMed  CrossRef  Google Scholar 

  165. Ofner P, Bosland MC, Vena RL. Differential effects of diethylstilbestrol and estradiol-17 beta in combination with testosterone on rat prostate lobes. Toxicol Appl Pharmacol. 1992;112:300–9.

    CAS  PubMed  CrossRef  Google Scholar 

  166. Wang Y, Hayward SW, Donjacour AA, et al. Hormonal carcinogenesis of the Rb-knockout mouse prostate. Cancer Res. 2000;60:6008–17.

    CAS  PubMed  Google Scholar 

  167. Spearow JL, Doemeny P, Sera R, Leffler R, Barkley M. Genetic variation in susceptibility to endocrine disruption by estrogen in mice. Science. 1999;285:1259–61.

    CAS  PubMed  CrossRef  Google Scholar 

  168. Santen RJ, Santner SJ, Pauley RJ, et al. Estrogen production via the aromatase enzyme in breast carcinoma: which cell type is responsible? J Steroid Biochem Mol Biol. 1997;61:267–71.

    CAS  PubMed  CrossRef  Google Scholar 

  169. Simpson ER, Mahendroo MS, Nichols JE, Bulun SE. Aromatase gene expression in adipose tissue: relationship to breast cancer. Int J Fertil Menopausal Stud. 1994;39:75–83.

    PubMed  Google Scholar 

  170. Pollard M, Snyder DL, Luckert PH. Dihydrotestosterone does not induce prostate adenocarcinoma in L-W rats. Prostate. 1987;10:325–31.

    CAS  PubMed  CrossRef  Google Scholar 

  171. Prins GS, Birch L. Neonatal estrogen exposure up-regulates estrogen receptor expression in the developing and adult rat prostate lobes. Endocrinology. 1997;138:1801–9.

    CAS  PubMed  Google Scholar 

  172. vom Saal FS, Timms BG, Montano MM, et al. Prostate enlargement in mice due to fetal exposure to low doses of estradiol or diethylstilbestrol and opposite effects at high doses. Proc Natl Acad Sci U S A. 1997;94:2056–61.

    PubMed Central  CrossRef  Google Scholar 

  173. Prins GS, Birch L. The developmental pattern of androgen receptor expression in rat prostate lobes is altered after neonatal exposure to estrogen. Endocrinology. 1995;136:1303–14.

    CAS  PubMed  Google Scholar 

  174. Pylkkanen L, Makela S, Valve E, et al. Prostatic dysplasia associated with increased expression of c-myc in neonatally estrogenized mice. J Urol. 1993;149:1593–601.

    CAS  PubMed  Google Scholar 

  175. Salo LK, Makela SI, Stancel GM, Santti RS. Neonatal exposure to diethylstilbestrol permanently alters the basal and 17 beta-estradiol induced expression of c-fos proto-oncogene in mouse urethroprostatic complex. Mol Cell Endocrinol. 1997;126:133–41.

    CAS  PubMed  CrossRef  Google Scholar 

  176. Colborn T, vom Saal FS, Soto AM. Developmental effects of endocrine-disrupting chemicals in wildlife and humans. Environ Health Perspect. 1993;101:378–84.

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  177. Peretz J, Vrooman L, Ricke WA, et al. Bisphenol a and reproductive health: update of experimental and human evidence, 2007-2013. Environ Health Perspect. 2014;122:775–86.

    PubMed  PubMed Central  Google Scholar 

  178. Prins GS, Hu WY, Shi GB, 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  CrossRef  CAS  Google Scholar 

  179. Bonkhoff H, Fixemer T, Hunsicker I, Remberger K. Estrogen receptor expression in prostate cancer and premalignant prostatic lesions. Am J Pathol. 1999;155:641–7.

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  180. Leav I, Lau KM, Adams JY, et al. Comparative studies of the estrogen receptors beta and alpha and the androgen receptor in normal human prostate glands, dysplasia, and in primary and metastatic carcinoma. Am J Pathol. 2001;159:79–92.

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  181. 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  CrossRef  Google Scholar 

  182. Fixemer T, Remberger K, Bonkhoff H. Differential expression of the estrogen receptor beta (ERbeta) in human prostate tissue, premalignant changes, and in primary, metastatic, and recurrent prostatic adenocarcinoma. Prostate. 2003;54:79–87.

    CAS  PubMed  CrossRef  Google Scholar 

  183. Horvath LG, Henshall SM, Lee CS, et al. Frequent loss of estrogen receptor-beta expression in prostate cancer. Cancer Res. 2001;61:5331–5.

    CAS  PubMed  Google Scholar 

  184. Signoretti S, Loda M. Estrogen receptor beta in prostate cancer: brake pedal or accelerator? Am J Pathol. 2001;159:13–6.

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  185. McPherson SJ, Ellem SJ, Simpson ER, et al. Essential role for estrogen receptor beta in stromal-epithelial regulation of prostatic hyperplasia. Endocrinology. 2007;148:566–74.

    CAS  PubMed  CrossRef  Google Scholar 

  186. Krege JH, Hodgin JB, Couse JF, et al. Generation and reproductive phenotypes of mice lacking estrogen receptor beta. Proc Natl Acad Sci U S A. 1998;95:15677–82.

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  187. Montano MM, Deng H, Liu M, Sun X, Singal R. Transcriptional regulation by the estrogen receptor of antioxidative stress enzymes and its functional implications. Oncogene. 2004;23:2442–53.

    CAS  PubMed  CrossRef  Google Scholar 

  188. Montano MM, Katzenellenbogen BS. The quinone reductase gene: a unique estrogen receptor-regulated gene that is activated by antiestrogens. Proc Natl Acad Sci U S A. 1997;94:2581–6.

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  189. Montano MM, Wittmann BM, Bianco NR. Identification and characterization of a novel factor that regulates quinone reductase gene transcriptional activity. J Biol Chem. 2000;275:34306–13.

    CAS  PubMed  CrossRef  Google Scholar 

  190. Sasaki M, Kaneuchi M, Fujimoto S, Tanaka Y, Dahiya R. Hypermethylation can selectively silence multiple promoters of steroid receptors in cancers. Mol Cell Endocrinol. 2003;202:201–7.

    CAS  PubMed  CrossRef  Google Scholar 

  191. Zhu X, Leav I, Leung YK, et al. Dynamic regulation of estrogen receptor-beta expression by DNA methylation during prostate cancer development and metastasis. Am J Pathol. 2004;164:2003–12.

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  192. Domann FE, Futscher BW. Flipping the epigenetic switch. Am J Pathol. 2004;164:1883–6.

    CAS  PubMed  PubMed Central  CrossRef  Google Scholar 

  193. Ip MM, Milholland RJ, Rosen F. Functionality of estrogen receptor and tamoxifen treatment of R3327 Dunning rat prostate adenocarcinoma. Cancer Res. 1980;40:2188–93.

    CAS  PubMed  Google Scholar 

  194. Noble RL. Production of Nb rat carcinoma of the dorsal prostate and response of estrogen-dependent transplants to sex hormones and tamoxifen. Cancer Res. 1980;40:3547–50.

    CAS  PubMed  Google Scholar 

  195. Kangas L. Review of the pharmacological properties of toremifene. J Steroid Biochem. 1990;36:191–5.

    CAS  PubMed  CrossRef  Google Scholar 

  196. Warri AM, Huovinen RL, Laine AM, Martikainen PM, Harkonen PL. Apoptosis in toremifene-induced growth inhibition of human breast cancer cells in vivo and in vitro. J Natl Cancer Inst. 1993;85:1412–8.

    CAS  PubMed  CrossRef  Google Scholar 

  197. Raghow S, Hooshdaran MZ, Katiyar S, Steiner MS. Toremifene prevents prostate cancer in the transgenic adenocarcinoma of mouse prostate model. Cancer Res. 2002;62:1370–6.

    CAS  PubMed  Google Scholar 

  198. Cunha GR, Wang YZ, Hayward SW, Risbridger GP. Estrogenic effects on prostatic differentiation and carcinogenesis. Reprod Fertil Dev. 2001;13:285–96.

    CAS  PubMed  CrossRef  Google Scholar 

  199. Price D, Stein B, Sieber P, 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.

    Google Scholar 

  200. Taneja SS, Morton R, Barnette G, 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 Oncoly. 2013;31:523–9.

    CAS  CrossRef  Google Scholar 

  201. Bosland MC. The role of steroid hormones in prostate carcinogenesis. J Natl Cancer Inst Monogr. 2000;39–66.

    Google Scholar 

  202. Russo J, Fernandez SV, Russo PA, et al. 17-Beta-estradiol induces transformation and tumorigenesis in human breast epithelial cells. FASEB J. 2006;20:1622–34.

    CAS  PubMed  CrossRef  Google Scholar 

  203. Nomura AM, Kolonel LN. Prostate cancer: a current perspective. Epidemiol Rev. 1991;13:200–27.

    CAS  PubMed  Google Scholar 

  204. Lee MM, Gomez SL, Chang JS, et al. Soy and isoflavone consumption in relation to prostate cancer risk in China. Cancer Epidemiol Biomarkers Prev. 2003;12:665–8.

    CAS  PubMed  Google Scholar 

  205. Makela SI, Pylkkanen LH, Santti RS, Adlercreutz H. Dietary soybean may be antiestrogenic in male mice. J Nutr. 1995;125:437–45.

    CAS  PubMed  Google Scholar 

  206. Wang J, Eltoum IE, Lamartiniere CA. Dietary genistein suppresses chemically induced prostate cancer in Lobund-Wistar rats. Cancer Lett. 2002;186:11–8.

    CAS  PubMed  CrossRef  Google Scholar 

  207. Mentor-Marcel R, Lamartiniere CA, Eltoum IE, Greenberg NM, Elgavish A. Genistein in the diet reduces the incidence of poorly differentiated prostatic adenocarcinoma in transgenic mice (TRAMP). Cancer Res. 2001;61:6777–82.

    CAS  PubMed  Google Scholar 

  208. Schulz P, Bauer HW, Brade WP, Keller A, Fittler F. Evaluation of the cytotoxic activity of diethylstilbestrol and its mono- and diphosphate towards prostatic carcinoma cells. Cancer Res. 1988;48:2867–70.

    CAS  PubMed  Google Scholar 

  209. Dahllof B, Billstrom A, Cabral F, Hartley-Asp B. Estramustine depolymerizes microtubules by binding to tubulin. Cancer Res. 1993;53:4573–81.

    CAS  PubMed  Google Scholar 

  210. Li Y, Sarkar FH. Gene expression profiles of genistein-treated PC3 prostate cancer cells. J Nutr. 2002;132:3623–31.

    CAS  PubMed  Google Scholar 

  211. Kuwajerwala N, Cifuentes E, Gautam S, et al. Resveratrol induces prostate cancer cell entry into s phase and inhibits DNA synthesis. Cancer Res. 2002;62:2488–92.

    CAS  PubMed  Google Scholar 

  212. Kim IY, Kim BC, Seong DH, 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 

  213. Qadan LR, Perez-Stable CM, Anderson C, et al. 2-Methoxyestradiol induces G2/M arrest and apoptosis in prostate cancer. Biochem Biophys Res Commun. 2001;285:1259–66.

    CAS  PubMed  CrossRef  Google Scholar 

  214. Shimada K, Nakamura M, Ishida E, Kishi M, Konishi N. Requirement of c-jun for testosterone-induced sensitization to N-(4-hydroxyphenyl)retinamide-induced apoptosis. Mol Carcinog. 2003;36:115–22.

    CAS  PubMed  CrossRef  Google Scholar 

  215. LaVallee TM, Zhan XH, Johnson MS, et al. 2-Methoxyestradiol up-regulates death receptor 5 and induces apoptosis through activation of the extrinsic pathway. Cancer Res. 2003;63:468–75.

    CAS  PubMed  Google Scholar 

  216. Mor G, Kohen F, Garcia-Velasco J, et al. Regulation of fas ligand expression in breast cancer cells by estrogen: functional differences between estradiol and tamoxifen. J Steroid Biochem Mol Biol. 2000;73:185–94.

    CAS  PubMed  CrossRef  Google Scholar 

  217. Rafi MM, Rosen RT, Vassil A, et al. Modulation of bcl-2 and cytotoxicity by licochalcone-A, a novel estrogenic flavonoid. Anticancer Res. 2000;20:2653–8.

    CAS  PubMed  Google Scholar 

  218. Bergan RC, Reed E, Myers CE, et al. A phase II study of high-dose tamoxifen in patients with hormone-refractory prostate cancer. Clin Cancer Res. 1999;5:2366–73.

    CAS  PubMed  Google Scholar 

  219. Hamilton M, Dahut W, Brawley O, et al. A phase I/II study of high-dose tamoxifen in combination with vinblastine in patients with androgen-independent prostate cancer. Acta Oncol. 2003;42:195–201.

    CAS  PubMed  CrossRef  Google Scholar 

  220. Lissoni P, Vigano P, Vaghi M, et al. A phase II study of tamoxifen in hormone-resistant metastatic prostate cancer: Possible relation with prolactin secretion. Anticancer Res. 2005;25:3597–9.

    CAS  PubMed  Google Scholar 

  221. Shazer RL, Jain A, Galkin AV, 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  CrossRef  Google Scholar 

  222. Stein S, Zoltick B, Peacock T, et al. Phase II trial of toremifene in androgen-independent prostate cancer: a Penn cancer clinical trials group trial. Am J Clin Oncol. 2001;24:283–5.

    CAS  PubMed  CrossRef  Google Scholar 

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Ricke, W.A., Williams, K., Wynder, J., Palapattu, G., Wang, Y., Cunha, G.R. (2017). Hormonal Carcinogenesis: The Role of Estrogens. In: Coleman, W., Tsongalis, G. (eds) The Molecular Basis of Human Cancer. Humana Press, New York, NY. https://doi.org/10.1007/978-1-59745-458-2_20

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