The transcription factor forkhead box Q1 (FoxQ1), which is overexpressed in different solid tumors, has emerged as a key player in the pathogenesis of breast cancer by regulating epithelial-mesenchymal transition, maintenance of cancer-stem like cells, and metastasis. However, the mechanism underlying oncogenic function of FoxQ1 is still not fully understood. In this study, we compared the RNA-seq data from FoxQ1 overexpressing SUM159 cells with that of empty vector-transfected control (EV) cells to identify novel mechanistic targets of this transcription factor. Consistent with published results in basal-like subtype, immunohistochemistry revealed upregulation of FoxQ1 protein in luminal-type human breast cancer tissue microarrays when compared to normal mammary tissues. Many previously reported transcriptional targets of FoxQ1 (e.g., E-cadherin, N-cadherin, fibronectin 1, etc.) were verified from the RNA-Seq analysis. FoxQ1 overexpression resulted in downregulation of genes associated with cell cycle checkpoints, M phase, and cellular response to stress/external stimuli as evidenced from the Reactome pathway analysis. Consequently, FoxQ1 overexpression resulted in S, G2M and mitotic arrest in basal-like SUM159 and HMLE cells, but not in luminal-type MCF-7 cells. There were differences in expression of cell cycle-associated proteins between FoxQ1 overexpressing SUM159 and MCF-7 cells. Finally, we show for the first time that FoxQ1 is a direct transcriptional regulator of interleukin (IL)-1, IL-8, and vascular endothelial growth factor in breast cancer cells. Chromatin immunoprecipitation revealed FoxQ1 occupancy at the promoters of IL-1, IL-8, and VEGF. In conclusion, the present study reports novel mechanistic targets of FoxQ1 in human breast cancer cells.

中文翻译：

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人类乳腺癌细胞中叉头盒Q1转录因子的新型机制目标。

在不同的实体瘤中过表达的转录因子叉头盒Q1（FoxQ1）已通过调节上皮-间质转化，癌干样细胞的维持和转移，成为乳腺癌发病机制中的关键角色。但是，FoxQ1致癌功能的潜在机制仍不完全清楚。在这项研究中，我们比较了过表达FoxQ1的SUM159细胞与空载体转染的对照（EV）细胞的RNA-seq数据，以确定该转录因子的新机制靶标。与已发表的基底样亚型的结果一致，免疫组织化学显示与正常乳腺组织相比，管腔型人乳腺癌组织微阵列中的FoxQ1蛋白上调。许多先前报道的FoxQ1转录靶标（例如E-cadherin，从RNA-Seq分析中验证了N-钙粘蛋白，纤连蛋白1等。从Reactome途径分析可以看出，FoxQ1的过表达导致与细胞周期检查点，M期相关的基因下调，以及细胞对应激/外部刺激的反应。因此，FoxQ1过表达导致基底样SUM159和HMLE细胞中的S，G2M和有丝分裂停滞，而在腔型MCF-7细胞中则没有。FoxQ1过表达的SUM159和MCF-7细胞之间的细胞周期相关蛋白表达存在差异。最后，我们首次证明FoxQ1是乳腺癌细胞中白介素（IL）-1，IL-8和血管内皮生长因子的直接转录调节因子。染色质的免疫沉淀显示FoxQ1在IL-1，IL-8和VEGF的启动子上占有。结论，