FOXK2 amplification and overexpression promotes breast cancer development and chemoresistance.
FOXK2 amplification and overexpression promotes breast cancer development and chemoresistance.
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FOXK2 扩增和过度表达可促进乳腺癌的发展和化疗耐药性。
DOI：
10.1101/2023.05.28.542643
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Zhang,Hong
中科院分区：
文献类型：
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作者：
Yu,Yang;Cao,Wen-Ming;Cheng,Feng;Shi,Zhongcheng;Han,Lili;Yi,Jin-Ling;daSilva,EdaiseM;Dopeso,Higinio;Chen,Hui;Yang,Jianhua;Wang,Xiaosong;Zhang,Chunchao;Zhang,Hong
通过DNA扩增/过表达激活癌基因在癌症的发生和发展中起着重要作用。17号染色体有许多与癌症相关的基因异常。这种细胞遗传学异常与乳腺癌预后不良密切相关。FOXK2基因位于17q25上，编码一个带有叉头DNA结合域的转录因子。通过对乳腺癌公共基因组数据集的综合分析，我们发现FOXK2在乳腺癌中经常被扩增和过表达。FOXK2在乳腺癌患者中的过表达与较差的总生存率相关。FOXK2敲低可显著抑制乳腺癌细胞的增殖、侵袭转移和非锚定生长，并导致G0/G1细胞周期阻滞。此外，FOXK2表达的抑制使乳腺癌细胞对一线抗肿瘤化疗敏感。更重要的是，FOXK2和PI3KCA与致癌突变（E545K或H1047R）共同过表达诱导非致瘤性MCF10A细胞的细胞转化，这表明FOXK2是乳腺癌的致癌基因，参与了PI3KCA驱动的肿瘤发生。我们的研究发现CCNE2、PDK1和雌激素受体α (ESR1)是MCF-7细胞中FOXK2的直接转录靶点。利用小分子抑制剂阻断CCNE2-和pdk1介导的信号通路对乳腺癌细胞具有协同抗肿瘤作用。此外，FOXK2转录靶点（CCNE2和PDK1）的基因敲低或抑制剂与PI3KCA抑制剂Alpelisib联合抑制FOXK2，对PI3KCA致癌突变的乳腺癌细胞显示出协同抗肿瘤作用。总之，我们提供了令人信服的证据，证明FOXK2在乳腺肿瘤发生中起致癌作用，靶向FOXK2介导的途径可能是乳腺癌的潜在治疗策略。
Activation of oncogenes through DNA amplification/overexpression plays an important role in cancer initiation and progression. Chromosome 17 has many cancer-associated genetic anomalies. This cytogenetic anomaly is strongly associated with poor prognosis of breast cancer. FOXK2 gene is located on 17q25 and encodes a transcriptional factor with a forkhead DNA binding domain. By integrative analysis of public genomic datasets of breast cancers, we found that FOXK2 is frequently amplified and overexpressed in breast cancers. FOXK2 overexpression in breast cancer patients is associated with poor overall survival. FOXK2 knockdown significantly inhibits cell proliferation, invasion and metastasis, and anchorage-independent growth, as well as causes G0/G1 cell cycle arrest in breast cancer cells. Moreover, inhibition of FOXK2 expression sensitizes breast cancer cells to frontline anti-tumor chemotherapies. More importantly, co-overexpression of FOXK2 and PI3KCA with oncogenic mutations (E545K or H1047R) induces cellular transformation in non-tumorigenic MCF10A cells, suggesting that FOXK2 is an oncogene in breast cancer and is involved in PI3KCA-driven tumorigenesis. Our study identified CCNE2, PDK1, and Estrogen receptor alpha (ESR1) as direct transcriptional targets of FOXK2 in MCF-7 cells. Blocking CCNE2- and PDK1-mediated signaling by using small molecule inhibitors has synergistic anti-tumor effects in breast cancer cells. Furthermore, FOXK2 inhibition by gene knockdown or inhibitors for its transcriptional targets (CCNE2 and PDK1) in combination with PI3KCA inhibitor, Alpelisib, showed synergistic anti-tumor effects on breast cancer cells with PI3KCA oncogenic mutations. In summary, we provide compelling evidence that FOXK2 plays an oncogenic role in breast tumorigenesis and targeting FOXK2-mediated pathways may be a potential therapeutic strategy in breast cancer.