FOXF2调控基底样乳腺癌转移的作用和机制

FOXF2 is a key transcription factor during embryonic development and tissue differentiation. It maintains tissue homeostasis by promoting the differentiation of mesenchymal cells and inhibiting the mesenchymal transformation of epithelial cells. Recent studies indicated that FOXF2 was involved in carcinogenesis and tumor progression. However, little is known about the role and mechanism of FOXF2 in tumor metastasis. Our previous study demonstrated that the down-regulation of FOXF2 could lead to disseminated metastasis of basal-like breast cancer both in clinical cases and orthotopic xenograft mouse model. Based on the correlation analysis of the gene expression profiles in breast cancer tissues and the prediction of the transcriptional regulated target gene of FOXF2, we will elucidate the effect and mechanism that FOXF2 inhibits the metastasis of basal-like breast cancer via transcriptional regulation of EMT signal, self-renewal and differentiation of the stem-like cancer cells. Furthermore, we will investigate whether FOXF2 can transcriptionally inhibit the expression of FOXC2 and FOXQ1 which are the regulated target gene of FOXF2 and can promote the metastasis in basal-like breast cancer. In addition, we will explore the effect of FOXF2 on reverse resistance for chemotherapy drugs in the basal-like breast cancer both in vivo and in vitro. Based on the study of clinical cases, we will evaluate the molecular diagnostic and prognoctic value of FOXF2 combined with FOXC2 and FOXQ1 in patients with basal-like breast cancer. Our findings will enrich the understanding of intrinsic biological characteristics and metastatic mechanisms of basal-like breast cancer, and will provide new strategy in molecular diagnosis and targeted therapy for basal-like breast cancer.

FOXF2是胚胎发育和组织分化的关键转录因子，通过促进间质细胞分化和抑制上皮细胞间质转化维持组织稳态。前期临床病例研究和动物实验均证实FOXF2在三阴性/基底样乳腺癌中表达下调显著增加播散性转移。在基于前期乳腺癌组织基因表达谱数据的基因间相关性分析和转录调控靶基因预测的基础上，通过体内外实验阐明FOXF2转录调控EMT信号、分化信号及干性诱导和维持信号促进干样癌细胞分化，从而抑制基底样乳腺癌转移的作用和机制。基于FOXF2促干样癌细胞分化作用，通过体内外实验评价其对基底样乳腺癌的耐药逆转作用；基于FOXF2转录抑制FOXC2和FOXQ1表达并拮抗二者的促基底样乳腺癌转移作用，通过临床病例研究评估FOXF2联合FOXC2/FOXQ1预测三阴性/基底样乳腺癌患者预后的分子诊断价值。研究结果将丰富对基底样乳腺癌内在生物特性和转移机制的理论认识，并有望为基于其生物学基础的诊断和治疗提供新的策略。

FOXF2是胚胎发育和组织分化中调节中胚层发育和间质细胞分化的多效性转录调控因子，特异性表达于邻近上皮细胞的间质细胞中，通过调控间质细胞与上皮细胞的相互作用维持上皮细胞极性和组织内环境稳态。本项目首先通过临床病例研究证实，FOXF2在乳腺原发癌组织中低表达与肿瘤分化差和早期远处转移相关。关于FOXF2在乳腺癌中的表达及生物学功能的研究发现，FOXF2在具有间质细胞特性的基底样乳腺癌（BLBC）细胞中高表达，而在上皮特性的非BLBC细胞中不表达或低表达；FOXF2在BLBC细胞中的表达缺乏则促进上皮-间质转化（EMT）和干性，进而形成早发的播散性转移；FOXF2抑制BLBC转移的同时，促进了细胞增殖。关于FOXF2抑制BLBC的EMT和转移的机制研究发现，FOXF2在BLBC细胞中可多效性转录抑制TWIST1、FOXC2、FOXQ1等EMT转录因子（EMT-TFs）表达，但在非BLBC中对这些EMT-TFs无调控作用；FOXF2在BLBC细胞中低表达可转录上调EMT-TFs表达，从而诱导肿瘤细胞EMT和干样细胞表型及化疗耐药，进而促进肿瘤细胞早发的播散性内脏转移。FOXF2/TWIST1和FOXF2/FOXC2 mRNA联合检测可更有效地预测三阴性乳腺癌（TNBC）患者预后。关于FOXF2调控的下游信号机制研究发现，FOXF2可直接转录抑制TGF-β、Wnt和Noch信号通路的关键分子TGF-β2/3、FZD1、Noch3表达，进而调控BLBC细胞的EMT和干性。关于FOXF2在BLBC细胞中多效性转录抑制EMT-TFs的机制研究发现，在BLBC细胞中FOXF2可募集NCOR1至其靶基因的启动子区抑制其表达，而在luminal乳腺癌细胞中FOXF2对NCOR1无募集作用。关于FOXF2表达的乳腺癌细胞亚型特异性机制研究发现，非BLBC细胞中FOXF2近启动子区呈高甲基化，从而影响上游激活性转录因子SP1和MAZ的结合，导致FOXF2在非BLBC细胞中表达沉默；而BLBC细胞FOXF2近启动子区为低甲基化，可被SP1和MAZ上调并介导其抑制转移但促进增殖的作用。因此，本研究揭示了FOXF2/EMT转录调控轴在BLBC转移中的关键作用，并为TNBC/BLBC患者预后预测和靶向治疗提供了新策略。