FOXF2调控乳腺癌骨转移的作用和机制

Bone metastasis is a frequent event in breast cancer patients, however, the pathogenesis and underlaying molecular mechanisms of organ-specific bone metastasis remain to be elucideted. Forkhead box F2 (FOXF2), a mesenchymal-specific transcription factor, plays key roles for maintenance of tissue homeostasis by promoting the differentiation of mesenchymal cells and inhibiting the mesenchymal transformation of epithelial cells during embryonic development and tissue differentiation. In our previous gene expression profiling date set and online data sets of primary breast cancer tissues, FOXF2 was found to be ectopic co-expressed with a set of genes coding proteins related with bone remodeling and bone matrix remodeling, and multiple genes in which are candidate transcriptional targets of FOXF2. Clinical evident indicated that high FOXF2 mRNA level in breast cancer tissues increased the risk of bone metastasis in breast cancer patients. In vitro experiments showed that ectopic over-expression of FOXF2 in breast cancer cells promoted the capacities of chemotaxis, adhesion, and anchorage independent clonal growth in bone microenvironment, as well as induction of osteoclastogenesis. These evident suggest that FOXF2 might control the generation of osteomimic feature of breast cancer cells to became “pre-selected” seeds of bone metastasis through pleiotropic transcriptional upregulation of bone remodeling- and bone matrix remodeling-related genes that modifie the bone tissues to form a suitable “pre-metastatic niches” soil by secreting factors. Besides the role of FOXF2 in promoting breast cancer bone metastasis, it may enhance the chemotherapy resistance due to the barrier of secreted bone matrix proteins. The aims of this study are to clarify the role of FOXF2 in promoting bone metastasis of breast cancer cells and underplaying molecular mechanisms by in vivo and in vitro experiments. The findings under the investigation of this project will improve the theoretical understanding regarding the mechanism of breast cancer bone metastasis, and will provide novel strategyes for the prediction and treatment of breast cancer bone metastasis.

乳腺癌具有嗜骨转移特性，其形成机制尚待阐明。前期基于乳腺原发癌组织基因表达谱数据分析，发现间质特异性转录因子FOXF2与一组骨及骨基质重塑相关基因呈异位共表达，且其中多个基因启动子区含FOXF2转录结合域；临床病例研究发现乳腺癌组织中FOXF2高表达增加骨转移风险；体外细胞学实验证实FOXF2在乳腺癌细胞中异位高表达促进骨转移潜能，提示FOXF2通过转录调控骨及骨基质重塑相关基因表达使乳腺癌细胞呈Osteomimic表型，形成嗜骨的preselectic“种子”，并通过分泌因子促进骨组织形成易于肿瘤细胞定植和生长的premetastatic niches “土壤”，从而促进乳腺癌细胞特异性骨转移，且由于骨基质蛋白屏障作用导致化疗抵抗。本研究拟通过体内外实验阐明FOXF2促进乳腺癌骨转移的作用和机制。研究结果将丰富对乳腺癌嗜骨转移机制的理论认识，并为乳腺癌骨转移风险预测和靶向治疗提供新策略。

骨是乳腺癌最常见的远处转移器官，晚期乳腺癌患者骨转移发生率高达80%，且主要形成溶骨性转移，严重影响患者的生活质量和生存期。目前，乳腺癌骨转移的机制尚未阐明，临床尚缺乏早期预测和有效治疗骨转移的方法。阐明乳腺癌嗜骨转移的分子机制，可以为预防和治疗骨转移提供新策略。本研究通过临床病例分析、体内动物实验和体外细胞学实验，证实FOXF2异位高表达促进Luminal乳腺癌和基底样乳腺癌（basal-like breast cancer，BLBC）细胞骨特异性转移，但抑制基底样乳腺癌（basal-like breast cancer，BLBC）细胞内脏转移；FOXF2促进乳腺癌骨转移机制研究发现，FOXF2可多效性转录激活骨发育和重塑相关信号分子BMP4/SMAD1以及在骨分化早期表达的骨相关基因，使乳腺癌细胞发生上皮-成骨转化（epithelial-osteogenic transition，EOT），形成嗜骨转移的 “种子”，并诱导骨组织形成预转移的“土壤”，从而易于向骨微环境趋化和粘附、在骨微环境中定植和生长、并诱导破骨细胞成熟，形成溶骨性骨转移。联合检测乳腺原发癌组织中FOXF2及其靶基因（如FOXF2/BMP4、FOXF2/SMAD1或FOXF2/CTSK）表达水平可预测乳腺癌骨特异性转移风险。在本项目研究及课题组前期研究基础上，我们进一步研究了FOXF2调控BLBC内脏转移的作用和机制，以及FOXF2上游的转录调节和信号调节机制。本课题组关于FOXF2调控乳腺癌转移的作用和机制的系统性研究结果提示，FOXF2在肿瘤进展过程中呈动态改变，其异常高表达促进骨转移，而表达缺失加速内脏转移。因而，在基于FOXF2及其上、下游调控轴的靶向治疗中，应充分考虑可能的副作用风险。