Disruption of STAT5A and NMI signaling axis leads to ISG20-driven metastatic mammary tumors.

Molecular dynamics of developmental processes are repurposed by cancer cells to support cancer initiation and progression. Disruption of the delicate balance between cellular differentiation and plasticity during mammary development leads to breast cancer initiation and metastatic progression. STAT5A is essential for differentiation of secretory mammary alveolar epithelium. Active STAT5A characterizes breast cancer patients for favorable prognosis. N-Myc and STAT Interactor protein (NMI) was initially discovered as a protein that interacts with various STATs; however, the relevance of these interactions to normal mammary development and cancer was not known. We observe that NMI protein is expressed in the mammary ductal epithelium at the onset of puberty and is induced in pregnancy. NMI protein is decreased in 70% of patient specimens with metastatic breast cancer compared to primary tumors. Here we present our finding that NMI and STAT5A cooperatively mediate normal mammary development. Loss of NMI in vivo caused a decrease in STAT5A activity in normal mammary epithelial as well as breast cancer cells. Analysis of STAT5A mammary specific controlled genetic program in the context of NMI knockout revealed ISG20 (interferon stimulated exonuclease gene 20, a protein involved in rRNA biogenesis) as an unfailing negatively regulated target. Role of ISG20 has never been described in metastatic process of mammary tumors. We observed that overexpression of ISG20 is increased in metastases compared to matched primary breast tumor tissues. Our observations reveal that NMI-STAT5A mediated signaling keeps a check on ISG20 expression via miR-17–92 cluster. We show that uncontrolled ISG20 expression drives tumor progression and metastasis.

发育过程的分子动力学被癌细胞重新利用，以支持癌症的发生和进展。乳腺发育过程中细胞分化和可塑性之间的微妙平衡被打破，会导致乳腺癌的发生和转移进展。STAT5A对分泌性乳腺腺泡上皮的分化至关重要。活跃的STAT5A是乳腺癌患者预后良好的特征。N - Myc和STAT相互作用蛋白（NMI）最初是作为一种与多种STAT相互作用的蛋白被发现的；然而，这些相互作用与正常乳腺发育和癌症的相关性尚不清楚。我们观察到NMI蛋白在青春期开始时在乳腺导管上皮中表达，并在妊娠期被诱导。与原发性肿瘤相比，70%的转移性乳腺癌患者标本中NMI蛋白减少。在此我们展示我们的发现：NMI和STAT5A协同介导正常乳腺发育。体内NMI的缺失导致正常乳腺上皮细胞以及乳腺癌细胞中STAT5A活性降低。在NMI基因敲除的背景下对STAT5A乳腺特异性调控的基因程序进行分析，发现ISG20（干扰素刺激的核酸外切酶基因20，一种参与rRNA生物合成的蛋白）是一个始终受到负调控的靶点。ISG20在乳腺肿瘤转移过程中的作用从未被描述过。我们观察到与匹配的原发性乳腺癌组织相比，ISG20的过表达在转移灶中增加。我们的观察结果表明，NMI - STAT5A介导的信号通过miR - 17 - 92簇对ISG20的表达进行调控。我们表明不受控制的ISG20表达会驱动肿瘤进展和转移。