The transcription factor NFAT1 and the oncogene MDM2 have crucial roles in breast cancer development, progression, and metastasis. We have recently discovered that NFAT1 activates MDM2 expression. Here, we identified a small molecule (named Inulanolide A) that dually inhibited both NFAT1 and MDM2 in breast cancer cells in vitro and in vivo. Unlike conventional MDM2 inhibitors, Inulanolide A (InuA) exerted its selective anticancer activity in both p53-dependent and -independent manners. InuA decreased cell proliferation and induced G2/M phase arrest and apoptosis in breast cancer cells; it also led to a decrease in MDM2, NFAT1 and proteins associated with cell proliferation, and an increase in apoptotic signal related proteins. In a mouse orthotopic model, JapA suppressed tumor growth and lung metastasis without host toxicity. Thus, InuA is a novel NFAT1 and MDM2 dual targeting agent and may be a clinical candidate for breast cancer therapy. This study also validates the effectiveness of dually targeting NFAT1 and MDM2 in breast cancer.

中文翻译：

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Inulanolide A作为NFAT1-MDM2途径的新型双重抑制剂，可用于乳腺癌治疗

转录因子NFAT1和癌基因MDM2在乳腺癌的发生，发展和转移中起着至关重要的作用。我们最近发现NFAT1激活MDM2表达。在这里，我们确定了一个小分子（称为Inulanolide A），该分子在体外和体内均能双重抑制乳腺癌细胞中的NFAT1和MDM2。与传统的MDM2抑制剂不同，Inulanolide A（InuA）以p53依赖性和非依赖性方式发挥其选择性的抗癌活性。InuA降低了乳腺癌细胞的细胞增殖并诱导了G2 / M期阻滞和凋亡。它也导致MDM2，NFAT1和与细胞增殖有关的蛋白质减少，以及与凋亡信号相关的蛋白质增加。在小鼠原位模型中，JapA抑制了肿瘤的生长和肺转移，而没有宿主毒性。因此，InuA是一种新型NFAT1和MDM2双重靶向药物，可能是乳腺癌治疗的临床候选药物。这项研究还验证了双重靶向NFAT1和MDM2在乳腺癌中的有效性。