Estrogens and Their Receptors in Prostate Cancer: Therapeutic Implications

Abstract

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.

Keywords: castrate resistant prostate cancer; estradiol; estradiol receptors; new drugs; prostate cancer.

Figure 1

Illustrates the putative role of ER (α or β) in PC.

Figure 2

Estrogen or androgen stimulation rapidly leads to extranuclear assembly of estrogen receptor (ERβ)/androgen receptor (AR)/Src ternary complex in LNCaP cells. Once fully activated, Src tyrosine kinase triggers activation of Ras and its dependent kinase cascade. Activation of this signaling pathway increases cyclin D1 expression and promotes cell cycle progression in LNCaP cells. As discussed in the main text, the transcriptional activity mediated by ERβ might overcome the non-transcriptional activity of the receptor, thereby leading to cell cycle arrest and/or apoptosis.