title: Role of prolactin/prolactin receptor signaling in human breast cancer.
abstract: Prolactin (PRL), a hormone utilized at both the endocrine and autocrine levels, stimulates breast epithelial growth, differentiation, and motility. Recent data at the cellular, epidemiologic, and genetic levels have implicated a significant role for this hormone in the pathogenesis of human breast cancer. A family of prolactin receptor (PRLr) isoforms mediates the effects of PRL in human tissue. Now numbering six, these isoforms are co-variably expressed to differing degrees in normal versus malignant tissues. Following ligand binding, proximal PRLr signaling is initiated by three tyrosine kinases, namely Jak2, Src, and Tec. Activation of these kinases results in the triggering of multiple signaling networks, many of which are integrated by the Stat5 transcription factor. Both tyrosine and serine phosphorylation regulate Stat5 activity, as does the interaction of this transcription factor with co-activators and -repressors within the nucleus. Recently our lab has discovered that Stat5 activity is also regulated by its direct interaction with the retrotranslocated complex of PRL and the peptidyl prolyl isomerase cyclophilin B. This interaction results in the release of a repressor of Stat5 DNA-binding, the Peptide Inhibitor of Activated Stat 3 (PIAS3). Taken together, these data suggest that the summated genomic and non-genomic signaling actions of the PRL/PRLr complex serve to trigger an orchestrated pattern of gene expression that contributes to mammary development and the pathobiology of breast cancer.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, 513 SC Labs, 422 Curie Boulevard, Philadelphia, PA 19104, USA. clevengc@mail.med.upenn.edu
authors.forename: Charles V
authors.initials: CV
authors.lastname: Clevenger