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a Department of Environmental Health, College of Medicine, University of Cincinnati, Cincinnati, Ohio 45267, USA b Department of Surgery, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA
Key Words: estrogen receptor • antiestrogens • selective estrogen receptor modulator • (SERM) • nuclear receptor coregulators • DNA methylation • developmental reprogramming • licorice • apigenin • phytoestrogen • apoptosis • oxidative stress • genomic damages • prostate cancer risk • hormonal therapy
Address for correspondence: Shuk-Mei Ho, Ph.D., Division of Environmental Genetics and Molecular Toxicology, Department of Environmental Health, College of Medicine, University of Cincinnati, Cincinnati, OH 45267. Voice: 513-558-5701; fax: 513-558-0071. e-mail: shuk-mei.ho{at}uc.edu
Mounting evidence supports a key role played by estrogen or estrogen in synergy with an androgen, in the pathogenesis of prostate cancer (PCa). New experimental data suggest that this process could begin as early as prenatal life. During adulthood, estrogen carcinogenicity is believed to be mediated by the combined effects of hormone-induced, unscheduled cell proliferation and bioactivation of estrogens to genotoxic carcinogens. Increased bioavailability of estrogen through age-dependent increases in conversion from androgen could also be a contributing factor. Individual variations and race-/ethnic-based differences in circulating or locally formed estrogens or in tissue estrogen responsiveness may explain differential PCa risk among individuals or different populations. Estrogen receptor (ER)-
 and ER- are the main mediators of estrogen action in the prostate. However, ER- is the first ER subtype expressed in the fetal prostate. During cancer development, ER- expression is first lost as tumors progress into high grade in the primary site. Yet, its reexpression occurs in all metastatic cases of PCa. A change in cytosine methylation in a regulatory CpG island located in the proximal promoter of ER- may constitute an "on/off" switch for reversible regulation of ER- expression. A variety of estrogenic/antiestrogenic/selective estrogen receptor modulator (SERM)-like compounds have been shown to use non-ERE pathways, such as tethering of ER- to NF- B binding proteins, Sp2, or Ap1 for gene transactivation. These findings open new avenues for drug design that now focuses on developing a new generation of estrogen-based PCa therapies with maximal proapoptotic action but few or no side effects.
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