Abnormal activity of human prolactin (PRL) and its membrane-associated receptor (PRLR) contributes to the progression of uterine carcinoma. However, the underlying mechanisms are not well understood, and current means of targeting the PRL/PRLR axis in uterine cancer are limited. Our integrated analyses using The Cancer Genome Atlas and Genotype-Tissue Expression (GTEx) databases demonstrated that a short form of PRLR (PRLR_SF) is the isoform predominantly expressed in human uterine cancers; expression of this PRLR_SF was elevated in uterine cancers in comparison with cancer-free uterine tissues. We hypothesized that the overexpression of PRLR_SF in uterine cancer cells contributes, in part, to the oncogenic activity of the PRL/PRLR axis. Next, we employed G129R, an antagonist of human PRL, to block the PRL/PRLR axis in both PTENwt and PTENmut orthotopic mouse models of uterine cancer. In comparison with control groups, treatment with G129R as monotherapy or in combination with paclitaxel resulted in a significant reduction of growth and progression of orthotopic uterine tumors. Results from protein profiling of uterine cancer cells and in vivo tumors revealed a set of new downstream targets for G129R. Our results showed that G129R induced sub-G0 population arrest, decreased nascent protein synthesis, and initiated FOXO3a/EIF-4EBP1–mediated cell death in both PTENwt and PTENmut uterine cancer cells. Collectively, our results show a unique pattern of PRLR_SF expression predominantly in uterine cancer. Moreover, FOXO3a and EIF-4EBP1 are important mediators of cell death following G129R treatment in uterine cancer models.

中文翻译：

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阻断催乳素受体的短形式诱导 FOXO3a/EIF-4EBP1 介导的子宫癌细胞死亡

人类催乳素 (PRL) 及其膜相关受体 (PRLR) 的异常活性有助于子宫癌的进展。然而，其潜在机制尚不清楚，目前针对子宫癌中 PRL/PRLR 轴的方法有限。我们使用癌症基因组图谱和基因型-组织表达 (GTEx) 数据库进行的综合分析表明，PRLR 的短形式 (PRLR_SF) 是主要在人类子宫癌中表达的同种型；与无癌子宫组织相比，这种 PRLR_SF 的表达在子宫癌中升高。我们假设子宫癌细胞中 PRLR_SF 的过度表达部分有助于 PRL/PRLR 轴的致癌活性。接下来，我们使用了 G129R，一种人类 PRL 的拮抗剂，在子宫癌的 PTENwt 和 PTENmut 原位小鼠模型中阻断 PRL/PRLR 轴。与对照组相比，G129R 作为单一疗法或与紫杉醇联合治疗可显着减少原位子宫肿瘤的生长和进展。子宫癌细胞和体内肿瘤的蛋白质分析结果揭示了 G129R 的一组新的下游靶标。我们的结果表明，G129R 在 PTENwt 和 PTENmut 子宫癌细胞中诱导亚 G0 种群停滞，减少新生蛋白质合成，并启动 FOXO3a/EIF-4EBP1 介导的细胞死亡。总的来说，我们的结果显示了主要在子宫癌中的 PRLR_SF 表达的独特模式。此外，FOXO3a 和 EIF-4EBP1 是子宫癌模型中 G129R 治疗后细胞死亡的重要介质。