Loss of expression of the transcription regulator DC-SCRIPT (Zfp366) is a prominent prognostic event in estrogen receptor-positive breast cancer patients. Studying the inherent link between breast morphogenesis and tumorigenesis, we recently reported that DC-SCRIPT affects normal mammary branching morphogenesis and mammary epithelium homeostasis. Here we investigated the molecular mechanism involved in DC-SCRIPT mediated regulation of FGF2 induced mammary branching morphogenesis in a 3D organoid culture system. Our data show that the delayed mammary organoid branching observed in DC-SCRIPT-/- organoids cannot be compensated for by increasing FGF2 levels. Interestingly, FGFR1, the dominant FGF2 receptor, was expressed at a significantly lower level in basal epithelial cells of DC-SCRIPT deficient organoids relative to wildtype organoids. A potential link between DC-SCRIPT and FGFR1 was further supported by the predicted locations of the DC-SCRIPT DNA binding motif at the Fgfr1 gene. Moreover, ERK1/2 phosphorylation downstream of the FGFR1 pathway was decreased in basal epithelial cells of DC-SCRIPT deficient organoids. Altogether, this study shows a relationship between DC-SCRIPT and FGFR1 related pERK signaling in modulating the branching morphogenesis of mammary organoids in vitro.

中文翻译：

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DC-SCRIPT通过调节FGFR1-pERK信号转导轴影响乳腺类器官分支形态发生。

在雌激素受体阳性的乳腺癌患者中，转录调节因子DC-SCRIPT（Zfp366）表达的丧失是一个重要的预后事件。研究乳房形态发生和肿瘤发生之间的内在联系，我们最近报道DC-SCRIPT影响正常的乳腺分支形态发生和乳腺上皮稳态。在这里，我们研究了在3D类器官培养系统中DC-SCRIPT介导的FGF2诱导的乳腺分支形态发生调控的分子机制。我们的数据表明，在DC-SCRIPT-/-类器官中观察到的延迟的乳腺类动物器官分支不能通过增加FGF2水平来补偿。有趣的是，相对于野生型类器官，DCR-SCRIPT缺陷型类器官的基底上皮细胞中的显着较低的水平是FGFR1（占主导的FGF2受体）表达。DC-SCRIPT和FGFR1之间的潜在联系进一步得到了DC-SCRIPT DNA结合基序在Fgfr1基因上的预测位置的支持。而且，在DC-SCRIPT缺陷型类器官的基底上皮细胞中，FGFR1途径下游的ERK1 / 2磷酸化降低。总而言之，这项研究显示了DC-SCRIPT与FGFR1相关的pERK信号传导在体外调节乳腺类器官的分支形态发生中的关系。