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Suppression of FOXM1 activities and breast cancer growth in vitro and in vivo by a new class of compounds.
npj Breast Cancer ( IF 6.5 ) Pub Date : 2019-11-29 , DOI: 10.1038/s41523-019-0141-7 Yvonne Ziegler 1 , Mary J Laws 1 , Valeria Sanabria Guillen 1 , Sung Hoon Kim 2 , Parama Dey 1 , Brandi P Smith 3 , Ping Gong 1 , Noah Bindman 2 , Yuechao Zhao 1 , Kathryn Carlson 2 , Mayuri A Yasuda 1 , Divya Singh 1 , Zhong Li 4 , Dorraya El-Ashry 5 , Zeynep Madak-Erdogan 3 , John A Katzenellenbogen 2 , Benita S Katzenellenbogen 1
npj Breast Cancer ( IF 6.5 ) Pub Date : 2019-11-29 , DOI: 10.1038/s41523-019-0141-7 Yvonne Ziegler 1 , Mary J Laws 1 , Valeria Sanabria Guillen 1 , Sung Hoon Kim 2 , Parama Dey 1 , Brandi P Smith 3 , Ping Gong 1 , Noah Bindman 2 , Yuechao Zhao 1 , Kathryn Carlson 2 , Mayuri A Yasuda 1 , Divya Singh 1 , Zhong Li 4 , Dorraya El-Ashry 5 , Zeynep Madak-Erdogan 3 , John A Katzenellenbogen 2 , Benita S Katzenellenbogen 1
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The transcription factor FOXM1 is upregulated and overexpressed in aggressive, therapy-resistant forms of hormone receptor-positive and triple negative breast cancers, and is associated with less good patient survival. FOXM1 signaling is also a key driver in many other cancers. Here, we identify a new class of compounds effective in suppressing FOXM1 activity in breast cancers, and displaying good potency for antitumor efficacy. The compounds bind directly to FOXM1 and alter its proteolytic sensitivity, reduce the cellular level of FOXM1 protein by a proteasome- dependent process, and suppress breast cancer cell proliferation and cell cycle progression and increase apoptosis. RNA-seq and gene set enrichment analyses indicate that the compounds decrease expression of FOXM1-regulated genes and suppress gene ontologies under FOXM1 regulation. Several compounds have favorable pharmacokinetic properties and show good tumor suppression in preclinical breast tumor models. These compounds may be suitable for further clinical evaluation in targeting aggressive breast cancers driven by FOXM1.
中文翻译：
新型化合物在体外和体内抑制FOXM1活性和乳腺癌的生长。
转录因子FOXM1在激进的，具有治疗抗性的激素受体阳性和三阴性乳腺癌中被上调和过表达，并且与患者的不良生存相关。FOXM1信号也是许多其他癌症的关键驱动因素。在这里，我们确定了一类新的化合物，可有效抑制乳腺癌中FOXM1的活性，并显示出良好的抗肿瘤功效。这些化合物直接与FOXM1结合并改变其蛋白水解敏感性，通过蛋白酶体依赖性过程降低FOXM1蛋白的细胞水平，并抑制乳腺癌细胞增殖和细胞周期进程并增加凋亡。RNA-seq和基因集富集分析表明，该化合物可降低FOXM1调控基因的表达并抑制FOXM1调控下的基因本体。几种化合物具有良好的药代动力学特性，并且在临床前乳腺肿瘤模型中显示出良好的肿瘤抑制作用。这些化合物可能适用于针对由FOXM1驱动的侵袭性乳腺癌的进一步临床评估。
更新日期：2019-11-29
中文翻译：
新型化合物在体外和体内抑制FOXM1活性和乳腺癌的生长。
转录因子FOXM1在激进的，具有治疗抗性的激素受体阳性和三阴性乳腺癌中被上调和过表达，并且与患者的不良生存相关。FOXM1信号也是许多其他癌症的关键驱动因素。在这里，我们确定了一类新的化合物，可有效抑制乳腺癌中FOXM1的活性，并显示出良好的抗肿瘤功效。这些化合物直接与FOXM1结合并改变其蛋白水解敏感性，通过蛋白酶体依赖性过程降低FOXM1蛋白的细胞水平，并抑制乳腺癌细胞增殖和细胞周期进程并增加凋亡。RNA-seq和基因集富集分析表明，该化合物可降低FOXM1调控基因的表达并抑制FOXM1调控下的基因本体。几种化合物具有良好的药代动力学特性，并且在临床前乳腺肿瘤模型中显示出良好的肿瘤抑制作用。这些化合物可能适用于针对由FOXM1驱动的侵袭性乳腺癌的进一步临床评估。
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