Prolactin regulation of the prostate gland: a female player in a male game

Abstract

Prolactin is best known for its actions on the mammary gland. However, circulating prolactin is also detected in males and its receptor (PRLR) is expressed in the prostate, suggesting that the prostate is a target of prolactin. Germline knockout of prolactin or its receptor has failed to reveal a key role for prolactin signaling in mouse prostate physiology. However, several studies involving rodent models and human prostate cell lines and specimens have supported the contribution of the canonical PRLR-Jak2-Stat5a/b pathway to prostate cancer tumorigenesis and progression. Increased expression of prolactin in the prostate itself (rather than changes in circulating prolactin levels) and crosstalk with androgen receptor (AR) signaling are potential mechanisms for increased Stat5a/b signaling in prostate cancer. In the mouse prostate, prolactin overexpression results in disorganized expansion of the basal/stem cell compartment, which has been proposed to house putative prostate tumor-initiating cells. These findings provide new insight into the molecular and cellular targets by which locally produced prolactin could contribute to prostate cancer initiation and progression. A number of pharmacological inhibitors targeting various levels of the PRLR-Jak2-Stat5a/b pathway have been developed and are entering clinical trials for advanced prostate cancer.

Fig 1. Potential mechanisms of autocrine Prl-induced prostate tumorigenesis

Mouse and human prostate epithelia are schematically represented. As determined using Pb-PRL transgenic mice, phosphorylated Stat5 (p-Stat5) colocalized with proliferating (Ki-67 positive) luminal cells (represented in blue). As the latter also produce Prl and express the PrlR, this suggests that proliferation of this compartment is mediated by direct autocrine/paracrine effects. The mechanisms underlying proliferation of the basal/stem cell compartment has yet to be elucidated. Since the basal cell marker p63 did not colocalize with p-Stat5, this either suggests that any direct effect of Prl on this compartment could be mediated by signaling pathways other than Stat5, and/or that indirect effects could involve Prl-induced production/secretion of certain growth factor(s) from other cell compartments (stroma, luminal cells). Similar mechanisms may take place in the human prostate, as increased production of local Prl and p-Stat5 have been correlated with Gleason score (see text). In contrast to the mouse, where basal cells are maintained and even amplified in Prl-induced prostate tumors, human prostate tumors lose basal cell markers (p63) in favor of tumor makers (AMACR) never shown in mouse prostate. Effects of Prl on human prostate basal cells have not been documented to our knowledge.

Fig 2. PrlR-signaling in prostate epithelium and current drug development strategies

The Stat5a/b pathway (see Box 2 for explanations) appears to be the major, if not the only, signaling pathway triggered by the PrlR in mouse and human prostate epithelial cells. Physical interactions between Stat5 and AR have been documented, providing a mechanistic basis for crosstalk between these two pathways resulting in reciprocal synergistic effects. Various levels of inhibition of this signaling cascade are in development (represented in yellow), which involve targeting of PrlR activation (competitive PrlR antagonist), Jak2 activity/stability (Jak2 inhibitors), and Stat5 DNA binding/expression (Stat5 inhibitors).