Li‐Yuan Yu‐Lee

Prolactin (PRL), a pituitary peptide hormone, is known to regulate diverse physiological functions via its effects on cellular processes such as proliferation, differentiation, and cell survival. All these activities are mediated by the PRL receptor (PRL-R), a member of the hematopoietin cytokine receptor superfamily. To understand PRL-dependent mitogenic signaling in T cells, we cloned PRL. PRL-R, one mediator of PRL signaling, signal transducer and activator of transcription (Stat) 5b, and a panel of PRL-inducible immediate early-response genes from T cells. We are employing one of these PRL-inducible genes, the transcription factor interferon regulatory factor-1 (IRF-1), a multifunctional immune regulator gene, as a tool to understand how PRL modulates T-cell proliferative responses. In investigating regulatory events along the PRL-R/Janus activating kinase (JAK)/Stat/IRF-1 signaling pathway, we show that Stat factors can activate as well as inhibit IRF-1 promoter activity and that cross talk between Stat and nuclear factor (NF)kappaB signaling pathways also regulates IRF-1 expression. In understanding how signaling pathways cross talk at the IRF-1 promoter, we obtained insights into how PRL can modulate immune and inflammatory responses. These findings have much broader implications, not only for cells in the immune system but also for other PRL-responsive cells and tissues.

TODAY it is stylish to remark with fascination at the multiple overlapping functions of interleukins, colonystimulating factors, and a host of other “cytokines” that have been discovered in recent years. As a reminder that this is not really a new observation, the first HBP hormone to be purified was PRL (1), and it was recognized to have such a variety of biological actions that by 1963 there had been created a “vast and confusing literature” (2) replete with multiple names for the same hormone and arguments about how many hormones were responsible for each biological activity. The pleiotropy of PRL actions prompted Bern and Nicoll (3) to suggest in 1968 that it be renamed either “versatilin” or “omnipotin” (3), and by 1980 more than 200 actions of PRL had been documented in the various vertebrate classes (4). Redundancies between actions of PRL and GH were widely appreciated by the 1950s, and the similarities of human (h) PRL and hGH actions resulted in such controversies that many doubted the existence of separate human PRL and GHs until hPRL was definitively purified by Friesen's group in 1972 (5).

Bone is the most common site of metastases from prostate cancer. The mechanism by which prostate cancer cells metastasize to bone is not fully understood, but interactions between prostate cancer cells and bone cells are thought to initiate the colonization of metastatic cells at that site. Here, we show that cadherin-11 (also known as osteoblast-cadherin) was highly expressed in prostate cancer cell line derived from bone metastases and had strong homophilic binding to recombinant cadherin-11 in vitro. Down-regulation of cadherin-11 in bone metastasis-derived PC3 cells with cadherin-11-specific short hairpin RNA (PC3-shCad-11) significantly decreased the adhesion of those cells to cadherin-11 in vitro. In a mouse model of metastasis, intracardiac injection of PC3 cells led to metastasis of those cells to bone. However, the incidence of PC3 metastasis to bone in this model was reduced greatly when the expression of cadherin-11 by those cells was silenced. The clinical relevance of cadherin-11 in prostate cancer metastases was further studied by examining the expression of cadherin-11 in human prostate cancer specimens. Cadherin-11 was not expressed by normal prostate epithelial cells but was detected in prostate cancer, with its expression increasing from primary to metastatic disease in lymph nodes and especially bone. Cadherin-11 expression was not detected in metastatic lesions that occur in other organs. Collectively, these findings suggest that cadherin-11 is involved in the metastasis of prostate cancer cells to bone.

The immunoregulatory properties of prolactin, a pituitary peptide hormone, have received renewed attention. The prolactin receptor, a member of the hematopoietin/cytokine receptor superfamily, is ubiquitously expressed by cells in the immune system. Certain subpopulations of lymphocytes synthesize and secrete biologically active prolactin, which suggests that prolactin can act as an autocrine and/or paracrine factor to modulate the activities of cells of the immune system. This review focuses on the molecular actions of prolactin in the immune system. Emphasis is given to recent information about the molecular mechanisms of prolactin receptor signal transduction, and the signaling molecules and prolactin-inducible target genes that participate in these responses. In particular, the prolactin-inducible interferon regulatory factor-1 gene and its roles in mediating diverse immune responses are highlighted.

Abstract Bone metastasis from prostate cancer can occur years after prostatectomy, due to reactivation of dormant disseminated tumor cells (DTC) in the bone, yet the mechanism by which DTCs are initially induced into a dormant state in the bone remains to be elucidated. We show here that the bone microenvironment confers dormancy to C4-2B4 prostate cancer cells, as they become dormant when injected into mouse femurs but not under the skin. Live-cell imaging of dormant cells at the single-cell level revealed that conditioned medium from differentiated, but not undifferentiated, osteoblasts induced C4-2B4 cellular quiescence, suggesting that differentiated osteoblasts present locally around the tumor cells in the bone conferred dormancy to prostate cancer cells. Gene array analyses identified GDF10 and TGFβ2 among osteoblast-secreted proteins that induced quiescence of C4-2B4, C4-2b, and PC3-mm2, but not 22RV1 or BPH-1 cells, indicating prostate cancer tumor cells differ in their dormancy response. TGFβ2 and GDF10 induced dormancy through TGFβRIII to activate phospho-p38MAPK, which phosphorylates retinoblastoma (RB) at the novel N-terminal S249/T252 sites to block prostate cancer cell proliferation. Consistently, expression of dominant-negative p38MAPK in C4-2b and C4-2B4 prostate cancer cell lines abolished tumor cell dormancy both in vitro and in vivo. Lower TGFβRIII expression in patients with prostate cancer correlated with increased metastatic potential and decreased survival rates. Together, our results identify a dormancy mechanism by which DTCs are induced into a dormant state through TGFβRIII–p38MAPK–pS249/pT252–RB signaling and offer a rationale for developing strategies to prevent prostate cancer recurrence in the bone. Significance: These findings provide mechanistic insights into the dormancy of metastatic prostate cancer in the bone and offer a rationale for developing strategies to prevent prostate cancer recurrence in the bone. Cancer Res; 78(11); 2911–24. ©2018 AACR.