Blockade of the short-form of prolactin receptor induces FOXO3a/EIF-4EBP1-mediated cell death in uterine cancer.

Abnormal activity of human prolactin (PRL) and its membrane-associated receptor (PRLR) contribute 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 TCGA and 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 to 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. Besides, our results showed that G129R induced G0/G1 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.