Sackmann-Sala Lucila, Goffin Vincent
Inserm U1151, Institut Necker Enfants Malades, Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris, France,
Adv Exp Med Biol. 2015;846:221-42. doi: 10.1007/978-3-319-12114-7_10.
The physiological role of prolactin (PRL) in the prostate gland is not clearly understood. Genetically-modified mouse models that have invalidated actors of the PRL signaling axis failed to identify an essential regulatory function on this tissue. However, a large body of evidence suggests an important role for PRL in prostate tumorigenesis. Mainly through the activation of its downstream target STAT5, PRL can induce growth and survival of prostate cancer cells and tissues in several experimental settings. In the clinic, PRL expression and STAT5 activation in human prostate tumors correlate with disease severity. Available data point to a role of local (autocrine/paracrine) rather than circulating (endocrine) PRL in the induction of disease progression. In mice, transgenic expression of PRL in the prostate leads to enhanced epithelial hyperplasia and dysplasia, with amplification of basal/stem cells which have been recently identified as prostate cancer-initiating cells. Thus, targeting PRL receptor (PRLR)/STAT5 signaling may provide an alternative therapy for the treatment of prostate cancer. Corresponding targeted therapies currently in preclinical development include antagonists or blocking antibodies for the PRLR and small molecule inhibitors directed against the tyrosine kinase JAK2 upstream of STAT5. Present efforts are aimed at validating these therapies for the treatment of prostate cancer, while understanding the mechanisms of disease progression induced by PRL/STAT5.
催乳素（PRL）在前列腺中的生理作用尚不清楚。使PRL信号轴相关因子失活的基因改造小鼠模型未能确定其对该组织的重要调节功能。然而，大量证据表明PRL在前列腺肿瘤发生中起重要作用。在多种实验环境中，PRL主要通过激活其下游靶点信号转导子和转录激活子5（STAT5），诱导前列腺癌细胞和组织的生长与存活。在临床上，人前列腺肿瘤中PRL的表达和STAT5的激活与疾病严重程度相关。现有数据表明，局部（自分泌/旁分泌）而非循环（内分泌）PRL在疾病进展诱导中起作用。在小鼠中，前列腺中PRL的转基因表达导致上皮增生和发育异常加剧，基底/干细胞扩增，而这些细胞最近被确定为前列腺癌起始细胞。因此，靶向催乳素受体（PRLR）/STAT5信号通路可能为前列腺癌的治疗提供一种替代疗法。目前处于临床前开发阶段的相应靶向疗法包括PRLR的拮抗剂或阻断抗体以及针对STAT5上游酪氨酸激酶JAK2的小分子抑制剂。目前的工作旨在验证这些疗法对前列腺癌的治疗效果，同时了解PRL/STAT5诱导疾病进展的机制。
