In the era of precision medicine, the identification of new targets is a constant challenge to improve cancer therapy. Preclinical investigations, epidemiological studies and analyses of tissue specimens from patients strongly support the contribution of prolactin receptor (PRLR) signaling to breast and prostate tumorigenesis and cancer progression. Although a clear causative link with mutations of the genes encoding prolactin or its receptor is lacking, increased PRLR signaling in these cancers can be assessed by the overexpression of cognate proteins and is often confirmed by over-activation of downstream signaling effectors. Nevertheless, the PRLR neutralizing antibody LFA102 tested recently in a Phase I trial in advanced, PRLR-positive prostate cancer and breast cancer patients failed to provide any clinical benefit. This underlines the need to better understand the actual impact of PRLR signaling on the progression of these cancers. Canonical PRLR-triggered signaling cascades include STAT5A/B, ERK1/2, PI3K/Akt, FAK and Src family kinases. Recent studies suggested that the nature and the outcome of PRLR signaling might be markedly different in breast than in prostate cancer. In the latter, like in many organs, PRLR/STAT5 signaling acts as a pro-tumorigenic pathway. In particular, it promotes the amplification of treatment-resistant prostate stem/progenitor cells, predicts early cancer recurrence and favors metastatic dissemination. In contrast, PRLR/STAT5 signaling was recently proposed to prevent breast cancer cell dissemination and to predict favorable clinical outcomes. While there is no evidence that pathways other than STAT5 are activated by prolactin in the prostate, these alternate signaling cascades may be primarily responsible for the pro-tumorigenic effects of prolactin in breast cancer. If these conclusions are confirmed in future studies, the therapeutic targeting of PRLR signaling in breast and prostate cancer may warrant the development of organ-specific strategies.

在精密医学时代，确定新的靶标一直是改善癌症治疗的持续挑战。临床前研究，流行病学研究和患者组织标本分析强烈支持催乳素受体（PRLR）信号对乳腺癌和前列腺癌的发生和癌症进展的贡献。尽管缺乏与催乳素或其受体编码基因突变的明确因果关系，但是可以通过同源蛋白的过表达来评估这些癌症中PRLR信号传导的增加，并且经常通过下游信号传导效应子的过度激活来证实。尽管如此，最近在一项I期试验中在晚期PRLR阳性前列腺癌和乳腺癌患者中测试的PRLR中和抗体LFA102未能提供任何临床益处。这强调需要更好地了解PRLR信号传导对这些癌症进展的实际影响。典型的PRLR触发的信号级联包括STAT5A / B，ERK1 / 2，PI3K / Akt，FAK和Src家族激酶。最近的研究表明，PRLR信号传导的性质和结果在乳腺癌中可能与在前列腺癌中明显不同。在后者中，就像在许多器官中一样，PRLR / STAT5信号转导是促肿瘤发生的途径。特别是，它可以促进对治疗有抵抗力的前列腺干/祖细胞的扩增，预测癌症的早期复发并有利于转移性传播。相反，最近提出了PRLR / STAT5信号传导，以预防乳腺癌细胞的传播并预测良好的临床结果。尽管没有证据表明泌乳素在前列腺中激活了除STAT5以外的其他途径，但是这些交替的信号级联可能主要归因于催乳素在乳腺癌中的促肿瘤作用。如果这些结论在未来的研究中得到证实，则PRLR信号在乳腺癌和前列腺癌中的治疗靶点可能需要发展器官特异性策略。