Estrogen Action and Prostate Cancer

Jason L Nelles; Wen-Yang Hu; Gail S Prins

Disclosures

Expert Rev Endocrinol Metab. 2011;6(3):437-451. 

In This Article

Abstract and Introduction

Abstract

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.

Introduction

As the most common noncutaneous form of cancer in men, prostate cancer is the subject of over US$300 million in research funding annually from both the NIH and the National Cancer Institute in the USA, with comparable funding levels in other nations worldwide.[201,202] Despite these significant efforts, the exact mechanism of carcinogenesis is unknown, although it is believed to involve a combination of dietary, environmental, genetic, lifestyle and hormonal causes. While the hormonal regulation of prostate cancer has been studied for over 75 years, the focus has largely been on androgen action. More recent research increasingly suggests a role of estrogen in the etiology and progression of prostate cancer and this article will highlight the evidence on this topic.

Huggins first demonstrated the androgenic dependence of prostate cancer as a potential cause, as well as a point of intervention and therapy, ultimately leading to a Nobel prize in 1966.[1,2] The finding that castration caused regression of metastatic prostate cancer has led to decades of research on the role of androgens in prostate cancer, as well as anti-androgen therapy being a mainstay treatment for metastatic disease[3,4] and neoadjuvant therapy prior to treatment in locally advanced disease.[5] In the early era of prostate cancer research, the role of estrogen was primarily seen as an indirect anti-androgen action mediated through feedback inhibition of hypothalamic luteinizing hormone (LHRH) and pituitary luteinizing hormone (LH) release, resulting in decreased testicular androgen synthesis and release. Consequently, administration of exogenous estrogens such as the nonmetabolized diethylstilbestrol (DES) was used to reduce circulating androgens to castrate levels in patients with advanced prostate cancer.[4] Moreover, this method of effective 'chemical castration' was noted to lower the incidence of bone mineral density loss, a known complication of other forms of androgen deprivation therapy that also reduce the level of circulating endogenous estrogen.[6,3] This highlights the fact that estrogens and estrogen analogs play important physiologic roles in normal, healthy adult males.[3] The ability of estrogens to treat or prevent prostate cancer is under continued investigation. It was recently demonstrated that DES may be able to directly affect prostate cancer cell division by inhibiting telemorase.[7] In a xenograft model with human prostate cancer cells injected into castrated severe combined immune-deficient mice, estrogen appears to suppress tissue androgen levels as well as tumor growth, independent of estrogen receptor (ER) blockade.[8] As discussed later, the effects of phytoestrogens have also been investigated for several years as potential agents to prevent prostate cancer.

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