PDF(Pubmed)
Abstract：
Oncogene activation through DNA amplification or overexpression is a crucial driver of cancer initiation and progression. The FOXK2 gene, located on chromosome 17q25, encodes a transcription factor with a forkhead DNA-binding domain. Analysis of genomic datasets reveals that FOXK2 is frequently amplified and overexpressed in breast cancer, correlating with poor patient survival. Knockdown of FOXK2 significantly inhibited breast cancer cell proliferation, migration, anchorage-independent growth, and delayed tumor growth in a xenograft mouse model. Additionally, inhibiting FOXK2 sensitized breast cancer cells to chemotherapy. Co-overexpression of FOXK2 and mutant PI3KCA transformed non-tumorigenic MCF-10A cells, suggesting a role for FOXK2 in PI3KCA-driven tumorigenesis. CCNE2, PDK1, and ESR1 were identified as transcriptional targets of FOXK2 in MCF-7 cells. Small-molecule inhibitors of CCNE2/CDK2 (dinaciclib) and PDK1 (dichloroacetate) exhibited synergistic anti-tumor effects with PI3KCA inhibitor (alpelisib) in vitro. Inhibition of FOXK2 by dinaciclib synergistically enhanced the anti-tumor effects of alpelisib in a xenograft mouse model. Collectively, these findings highlight the oncogenic function of FOXK2 and suggest that FOXK2 and its downstream genes represent potential therapeutic targets in breast cancer.
摘要：
通过DNA扩增或过表达激活癌基因是癌症发生和进展的关键驱动因素。FOXK2基因,位于染色体17q25上，编码具有叉头DNA结合域的转录因子。基因组数据集的分析表明，FOXK2在乳腺癌中经常被扩增和过表达。与患者生存率低有关。敲除FOXK2显著抑制乳腺癌细胞增殖,迁移,锚定独立生长，和在异种移植小鼠模型中延迟肿瘤生长。此外,抑制FOXK2使乳腺癌细胞对化疗敏感。共过表达FOXK2和突变型PI3KCA转化的非肿瘤性MCF-10A细胞，提示FOXK2在PI3KCA驱动的肿瘤发生中的作用。CCNE2、PDK1和ESR1被鉴定为MCF-7细胞中FOXK2的转录靶标。CCNE2/CDK2（dinaciclib）和PDK1（二氯乙酸）的小分子抑制剂与PI3KCA抑制剂（alpelisib）在体外表现出协同抗肿瘤作用。dinaciclib对FOXK2的抑制协同增强了alpelisib在异种移植小鼠模型中的抗肿瘤作用。总的来说，这些发现突出了FOXK2的致癌功能,并提示FOXK2及其下游基因代表了乳腺癌的潜在治疗靶点.
