Prolactin (PRL) and its receptor (PRLr) play important roles in the pathogenesis of breast cancer. Cyclophilin A (CypA) is a cis-trans peptidyl-prolyl isomerase (PPI) that is constitutively associated with the PRLr and facilitates the activation of the tyrosine kinase Jak2. Treatment with the non-immunosuppressive prolyl isomerase inhibitor NIM811 or CypA short hairpin RNA inhibited PRL-stimulated signaling, breast cancer cell growth, and migration. Transcriptomic analysis revealed that NIM811 inhibited two-thirds of the top 50 PRL-induced genes and a reduction in gene pathways associated with cancer cell signaling. In vivo treatment of NIM811 in a TNBC xenograft lessened primary tumor growth and induced central tumor necrosis. Deletion of CypA in the MMTV-PyMT mouse model demonstrated inhibition of tumorigenesis with significant reduction in lung and lymph node metastasis. The regulation of PRLr/Jak2-mediated biology by NIM811 demonstrates that a non-immunosuppressive prolyl isomerase inhibitor can function as a potential breast cancer therapeutic.

催乳素（PRL）及其受体（PRLr）在乳腺癌的发病机理中起重要作用。亲环蛋白A（CypA）是顺式-反式肽基-脯氨酰异构酶（PPI），与PRLr组成型缔合，并促进酪氨酸激酶Jak2的激活。用非免疫抑制的脯氨酰异构酶抑制剂NIM811或CypA短发夹RNA处理可抑制PRL刺激的信号传导，乳腺癌细胞生长和迁移。转录组学分析显示，NIM811抑制了PRL诱导的前50个基因中的三分之二，并减少了与癌细胞信号相关的基因途径。体内NIM811在TNBC异种移植物中的治疗减少了原发性肿瘤的生长并诱导了中央性肿瘤坏死。MMTV-PyMT小鼠模型中CypA的删除表明抑制肿瘤发生，肺和淋巴结转移明显减少。NIM811对PRLr / Jak2介导的生物学的调节表明，一种非免疫抑制的脯氨酰异构酶抑制剂可以作为潜在的乳腺癌治疗药物。