Differences in the relative abundances of the progesterone receptor (PGR) isoforms PGRA and PGRB are often observed in women with reproductive tract cancers. To assess the importance of the PGR isoform ratio in the maintenance of the reproductive tract, we generated mice that overexpress PGRA or PGRB in all PGR-positive tissues. Whereas few PGRA-overexpressing mice developed reproductive tract tumors, all PGRB-overexpressing mice developed ovarian neoplasms that were derived from ovarian luteal cells. Transcriptomic analyses of the ovarian tumors from PGRB-overexpressing mice revealed enhanced AKT signaling and a gene expression signature similar to those of human ovarian and endometrial cancers. Treating PGRB-overexpressing mice with the PGR antagonist RU486 stalled tumor growth and decreased the expression of cell cycle–associated genes, indicating that tumor growth and cell proliferation were hormone dependent in addition to being isoform dependent. Analysis of the PGRB cistrome identified binding events at genes encoding proteins that are critical regulators of mitotic phase entry. This work suggests a mechanism whereby an increase in the abundance of PGRB relative to that of PGRA drives neoplasia in vivo by stimulating cell cycling.

在患有生殖道癌症的女性中，经常观察到孕激素受体 (PGR) 亚型 PGRA 和 PGRB 相对丰度的差异。为了评估 PGR 同工型比例在维持生殖道中的重要性，我们培育了在所有 PGR 阳性组织中过度表达 PGRA 或 PGRB 的小鼠。虽然很少有 PGRA 过表达的小鼠出现生殖道肿瘤，但所有 PGRB 过表达的小鼠都会出现源自卵巢黄体细胞的卵巢肿瘤。对 PGRB 过表达小鼠卵巢肿瘤的转录组分析显示，AKT 信号传导增强，且基因表达特征与人类卵巢癌和子宫内膜癌相似。用 PGR 拮抗剂 RU486 治疗 PGRB 过度表达的小鼠，可以抑制肿瘤生长并降低细胞周期相关基因的表达，表明肿瘤生长和细胞增殖除了同工型依赖性外，还依赖于激素。对 PGRB 顺反子的分析确定了编码蛋白质的基因的结合事件，这些蛋白质是有丝分裂期进入的关键调节因子。这项工作提出了一种机制，即 PGRB 相对于 PGRA 丰度的增加通过刺激细胞循环来驱动体内肿瘤形成。