Estrogen action and prostate cancer

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.

Figure 1. Renal graft of human prostate stem/progenitor cells recombined with rat urogenital mesenchyme following 3 months of elevated estradiol with testosterone support given to the host nude mouse

A locally invasive tumor can be seen in a prostate tissue xenograft after explantation (A). The tumor was induced using estrogen plus testosterone supplementation after implanting human epithelial progenitor cells and rat urogenital mesenchyme under the renal capsule of a nude mouse. Histopathology reveals that this tumor is prostatic adenocarcinoma (B). Images from [Prings GS et al., Unpublished Data].

Figure 2. Diagram of proposed mechanisms of estrogenic carcinogenicity in the prostate

Numbers refer to references supporting the corresponding pathway of estrogenic action.