Progesterone receptor signaling in the microenvironment of endometrial cancer influences its response to hormonal therapy.
Progesterone receptor signaling in the microenvironment of endometrial cancer influences its response to hormonal therapy.
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DOI：
10.1158/0008-5472.can-13-0930
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发表时间：
2013-08-01
期刊：
影响因子：
11.2
通讯作者：
Memarzadeh S
中科院分区：
文献类型：
--
作者：
Janzen DM;Rosales MA;Paik DY;Lee DS;Smith DA;Witte ON;Iruela-Arispe ML;Memarzadeh S
孕酮是孕激素受体(PR)的激动剂，是治疗子宫内膜癌的一种有效且耐受性良好的药物。由于缺乏预测激素敏感性的生物标志物，孕酮的临床应用受到限制。尽管孕酮在癌症治疗中有效，但其作用机制和作用部位仍不清楚。使用由临床相关的基因变化驱动的体内子宫内膜癌小鼠模型，但对激素治疗的二分性反应，我们证明了通过间质PR的信号转导是孕激素抗肿瘤作用的必要和充分。PTEN上皮缺失(PTENKO)所致的子宫内膜癌对激素敏感，间质PR表达丰富。在这些肿瘤中，作为单个基因改变的PR间质缺失诱导了孕激素抵抗，表明通过间质的旁分泌信号对于孕酮的治疗效果是必不可少的。当KRAS激活和PTEN缺失结合时，发生了一种激素难治性子宫内膜肿瘤，间质PR水平低(PTENKO/Kras)。PTENKO/Kras肿瘤对孕酮的先天抵抗源于肿瘤微环境中PR的甲基化。从结构性活性启动子表达的间质PR的添加使这些肿瘤对黄体酮治疗敏感。结果表明，通过基质PR的信号足以诱导激素反应。我们的研究结果表明，间质PR的表观遗传下调可能是激素难治性子宫内膜肿瘤对孕酮治疗增敏的潜在治疗靶点。基于这些结果，PR的间质表达可能成为预测激素治疗反应的可靠生物标志物。
Progesterone, an agonist for the progesterone receptor (PR), can be an efficacious and well-tolerated treatment in endometrial cancer. The clinical use of progesterone is limited due to the lack of biomarkers that predict hormone sensitivity. Despite its efficacy in cancer therapy, mechanisms and site of action for progesterone remain unknown. Using an in vivo endometrial cancer mouse model driven by clinically relevant genetic changes but dichotomous responses to hormonal therapy, we demonstrate that signaling through stromal PR is necessary and sufficient for progesterone anti-tumor effects. Endometrial cancers resulting from epithelial loss of PTEN (PTENKO) were hormone sensitive and had abundant expression of stromal PR. Stromal deletion of PR as a single genetic change in these tumors induced progesterone resistance indicating that paracrine signaling through the stroma is essential for the progesterone therapeutic effects. A hormone refractory endometrial tumor with low levels of stromal PR developed when activation of KRAS was coupled with PTEN-loss (PTENKO/Kras). The innate progesterone resistance in PTENKO/Kras tumors stemmed from methylation of PR in the tumor microenvironment. Add-back of stromal PR expressed from a constitutively active promoter sensitized these tumors to progesterone therapy. Results demonstrate that signaling through stromal PR is sufficient for inducing hormone responsiveness. Our findings suggest that epigenetic de-repression of stromal PR could be a potential therapeutic target for sensitizing hormone refractory endometrial tumors to progesterone therapy. Based on these results, stromal expression of PR may emerge as a reliable biomarker in predicting response to hormonal therapy.