Although prolactin (PRL) and growth hormone (GH) are prototypic pituitary hormones, they are also produced in several extrapituitary sites, including male and female reproductive tissues. However, the physiological relevance of these locally-produced hormones in these tissues is far from being well understood due to unknown extrapituitary PRL/GH gene regulation and detection/quantification issues. The amplification of autocrine/paracrine PRL and/or GH signaling have been suggested to participate in tumorigenesis of various tissues, including prostate, mammary and endometrial cancers (1;2). Intriguingly, the molecular mechanisms of action of autocrine GH have been suggested to exhibit some differences compared to circulating (endocrine) GH, which could ultimately favor tumor progression and resistance to treatments. Within the past few years our Laboratory has focused on the mechanisms of action of locally-produced PRL on prostate tumorigenesis (3). We use Pb-PRL transgenic mice that express rat PRL under the control of the prostate-specific probasin promoter leading to high PRL secretion by luminal epithelial cells (4). These mice develop benign prostate hyperplasia (BPH) slowly progressing to prostate intraepithelial neoplasia (PIN) that in some instances further evolve to locally invasive adenocarcinomas. Besides strong phosphorylation of Stat5, canonical signaling pathway of the PRL receptor, the major hallmark of these tumors involves anarchic amplification of the p63-positive basal epithelial cell compartment (5). This compartment is (one of) the niche(s) of prostate stem cells, whose involvement in prostate cancer initiation and recurrence has been recently assessed (6). Therefore, understanding the mechanism of basal/stem cell amplification due to local hyperprolactinemia may be of broad interest to develop new treatments for prostate cancer. Our data show that the activation of Stat5 signaling correlates with the occurrence of pathological basal/stem cell clusters in prostate tumors. Immunohistochemical analyses of these basal/stem cell clusters and immediately adjacent luminal cells demonstrated higher proliferation, Stat5 signaling, and expression of the stem/progenitor cell marker Sca-1 (stem cell antigen 1) compared to physiological basal cell clusters that are occasionally detected in wild-type prostates. These results suggest that basal cells clusters in Pb-PRL mice are more numerous and also display altered differentiation status. In addition, FACS analysis of isolated prostate cells revealed the existence of a new subpopulation of Sca-1-positive luminal cells that was amplified in Pb-PRL compared to wild-type prostates. These cells might represent luminal progenitors originating from the amplified basal/stem cell compartment and could be relevant in the initial steps of PRL-induced prostate tumorigenesis (7). Despite the obvious link between Stat5 signaling and histopathological features of Pb-PRL prostate tumors, our ongoing data indicate that mouse as well as human basal/stem cells are not direct targets of PRL. This suggests that the pathogenic phenotypes of Pb-PRL prostates are in fact mediated by paracrine messengers that we aim to identify.