人催乳素受体拮抗剂在乳腺肿瘤研究中的进展

Advances in research of human prolactin receptor antagonists in breast cancer

研究表明,不仅内分泌而且自分泌/旁分泌产生的催乳素(prolactin,PRL)在体外细胞水平、体内多种转基因和基因敲除动物模型以及一定数量的人群流行病学调查水平上,均与乳腺肿瘤的发病机制和病程进展有关。由于传统多巴胺类似物在乳腺肿瘤治疗过程中不能有效抑制垂体外PRL的产生,因此并不能有效抑制乳腺肿瘤的生长。为此,研究者设计了多种催乳素受体(prolactin receptor,PRLR)拮抗剂,包括内分泌PRL抑制剂、链突变拮抗剂、链嵌合体、PRL诱导的信号通路抑制剂等。链突变拮抗剂通过向天然PRL多肽链引入不同的突变来竞争性抑制内源性PRL与PRLR结合,是目前研究较多的一类PRLR拮抗剂。文中主要介绍链突变PRLR拮抗剂的发展、性质、作用机制以及在乳腺癌临床治疗中的应用前景。

contribute to the the cellular level tions through epi trapituitary sites, Increasing evidence has proved that both endocrine and autocrine/paracrine prolactin （PRL） pathogenesis and progression of human breast cancer. This contribution is confirmed by events at in vitro, from multiple transgenic and knockout models in vivo, and from sizable patient populademiologic analysis. Since traditional dopamine analogs are unable to inhibit PRL production in exthey can not inhibit the growth of breast cancer. Therefore, several broad categories of PRL/ PRLR antagonists are designed, including inhibitors of endocrine PRL elaboration, mutant ligand antagonists, ligand chimeras, and inhibitors of PRL-induced signaling and transactivation. Mutant ligand PRL receptor （PRLR） antagonists have been developed by introducing various mutations into its natural peptide ligand. They act through competing with endogenous PRL for receptor binding. In this paper, the development, character, mechanism and the potential clinical use of different mutant ligand PRLR antagonists are introduced.