Our previous studies demonstrated that the FOXM1 pathway is upregulated and the PPARA pathway downregulated in breast cancer (BC), and especially in the triple negative breast cancer (TNBC) subtype. Targeting the two pathways may offer potential therapeutic strategies to treat BC, especially TNBC which has the fewest effective therapies available among all BC subtypes. In this study we identified small molecule compounds that could modulate the PPARA and FOXM1 pathways in BC using two methods. In the first method, data were initially curated from the Connectivity Map (CMAP) database, which provides the gene expression profiles of MCF7 cells treated with different compounds as well as paired controls. We then calculated the changes in the FOXM1 and PPARA pathway activities from the compound-induced gene expression profiles under each treatment to identify compounds that produced a decreased activity in the FOXM1 pathway or an increased activity in the PPARA pathway. In the second method, the CMAP database tool was used to identify compounds that could reverse the expression pattern of the two pathways in MCF7 cells. Compounds identified as repressing the FOXM1 pathway or activating the PPARA pathway by the two methods were compared. We identified 19 common compounds that could decrease the FOXM1 pathway activity scores and reverse the FOXM1 pathway expression pattern, and 13 common compounds that could increase the PPARA pathway activity scores and reverse the PPARA pathway expression pattern. It may be of interest to validate these compounds experimentally to further investigate their effects on TNBCs.

我们之前的研究表明，在乳腺癌（BC），特别是三阴性乳腺癌（TNBC）亚型中，FOXM1 通路上调，PPARA 通路下调。针对这两种途径可能为 BC 的治疗提供潜在的治疗策略，尤其是 TNBC，它是所有 BC 亚型中有效疗法最少的。在这项研究中，我们使用两种方法鉴定了可以调节 BC 中 PPARA 和 FOXM1 通路的小分子化合物。在第一种方法中，数据最初是从连接图（CMAP）数据库中收集的，该数据库提供了用不同化合物处理的 MCF7 细胞以及配对对照的基因表达谱。然后，我们根据每种处理下化合物诱导的基因表达谱计算了 FOXM1 和 PPARA 途径活性的变化，以确定导致 FOXM1 途径活性降低或 PPARA 途径活性增加的化合物。在第二种方法中，使用CMAP数据库工具来识别可以逆转MCF7细胞中两种途径的表达模式的化合物。对两种方法鉴定为抑制 FOXM1 途径或激活 PPARA 途径的化合物进行了比较。我们鉴定了 19 种可以降低 FOXM1 通路活性评分并逆转 FOXM1 通路表达模式的常见化合物，以及 13 种可以增加 PPARA 通路活性评分并逆转 PPARA 通路表达模式的常见化合物。通过实验验证这些化合物以进一步研究它们对 TNBC 的影响可能很有意义。