Early work on the hormonal basis of prostate cancer focused on the role of androgens, but more recently estrogens have been implicated as potential agents in the development and progression of prostate cancer. In this article, we review the epidemiological, laboratory and clinical evidence that estrogen may play a causative role in human prostate cancer, as well as rodent and grafted in vivo models. We then review recent literature highlighting potential mechanisms by which estrogen may contribute to prostate cancer, including estrogenic imprinting and epigenetic modifications, direct genotoxicity, hyperprolactinemia, inflammation and immunologic changes, and receptor-mediated actions. We discuss the work performed so far separating the actions of the different known estrogen receptors (ERs), ERα and ERβ, as well as G-protein-coupled receptor 30 and their specific roles in prostate disease. Finally, we predict that future work in this field will involve more investigations into epigenetic changes, experiments using new models of hormonal dysregulation in developing human prostate tissue, and continued delineation of the roles of the different ER subtypes, as well as their downstream signaling pathways that may serve as therapeutic targets.
Our understanding of estrogen’s function in the pathogenesis, prevention and treatment of prostate cancer is still evolving. Although androgens are clearly involved in the progression of prostate cancer and anti-androgen therapy will probably remain the treatment of choice for metastastic disease for the foreseeable future, it is equally clear that androgens are only one side of the story. At least in rats, testosterone alone is necessary, but not sufficient, for the development of prostate cancer. It is only with the addition of estrogen that cancer can be reliably induced. In vivo and in vitro studies have identified multiple mechanisms of potential carcinogenesis, including direct genotoxicity, epigenotoxicity, hyperproloctinemia, chronic inflammation and prostatic ER-mediated changes that are in addition subject to disruption by environmental estrogens. Moreover, ample evidence for estrogen’s role in the development of human prostate cancer exists in the form of epidemiological data and associations between inflammation and cancer, which parallels findings in rodent prostates. The true role of estrogen in prostate cancer development and progression is probably complex and multifactorial, incorporating more than one of the mechanisms already described and with interplay between them.
A major challenge in clinical management of prostate cancer (PC) is to limit tumor growth and prevent metastatic spreading. Considerable efforts have been made to discover new compounds for PC therapy and recent years have seen promising progress in this field. Pharmacological approaches have been designed to achieve benefits in PC treatment and avoid the negative side effects resulting from administration of antagonists or agonists or new drugs. Nonetheless, the currently available therapies frequently induce resistance and PC progresses toward castration-resistant forms that can be caused by the androgen receptor reactivation and/or mutations, or derangement of signaling pathways. Preclinical and clinical findings have also shown that other nuclear receptors are frequently altered in PC. In this review, we focus on the role of estradiol/estradiol receptor (ER) axis, which controls PC growth and progression. Selective targeting of ER subtypes (α or β) may be an attractive way to limit the growth and spreading of prostatic cancer cells.
Estrogens in Prostate Carcinogenesis
Preclinical findings have shown that estradiol levels play an important role in PC pathogenesis. In aromatase knockout (KO) mice, which cannot metabolize androgens to estrogens, high testosterone levels only lead to prostatic hypertrophy and hyperplasia. In contrast, high estrogen and low testosterone levels induce inflammatory events and premalignant lesions (). These findings are corroborated by epidemiological studies, suggesting that estradiol serum levels and estradiol/testosterone (E/T) serum ratio impinge on PC initiation and progression. African-American men, who have high serum estradiol levels, exhibit a greater risk of developing PC (), and PC incidence increases during aging, since it is often diagnosed in elderly rather than young men ([19(). In elderly males, testosterone production by the testis declines, while estradiol concentration remains constant (). Consequently, the ratio between circulating and intraprostatic E/T increases.