肌动蛋白细胞骨架失调会导致细胞运动异常和肿瘤细胞转移扩散。本研究评估了 MRTF-A 野生型与功能突变体的过表达对乳腺癌 (BC) 细胞迁移和侵袭的影响。我们的研究表明，SRF 的相互作用对于 MRTF-A 诱导的 2D 和 3D 细胞迁移的促进至关重要，而 SAP 域功能对于 3D 细胞迁移的选择性非常重要。 MRTF-A 活性的增加与更有效的膜突出相关，这种表型主要归因于 SRF 与 MRTF 的相互作用。我们证明formin家族蛋白mDia2是MRTF刺激的肌动蛋白前沿聚合和细胞迁移的重要介质。临床 BC 标本的多重定量免疫组织化学和转录组分析进一步证明 MRTF 的核定位与癌细胞的恶性特征以及配对远处转移与原发肿瘤中 MRTF-SRF 基因特征的富集之间存在正相关性。总之，本研究建立了一种依赖 MRTF 的细胞迁移调节的新机制，并为 MRTF 活性与人类乳腺癌恶性程度增加之间的关联提供了证据，证明了未来开发 MRTF-SRF 转录复合物的特定小分子抑制剂的合理性乳腺癌的潜在治疗剂。

Dysregulated actin cytoskeleton gives rise to aberrant cell motility and metastatic spread of tumor cells. This study evaluates the effect of overexpression of wild-type vs functional mutants of MRTF-A on migration and invasion of breast cancer (BC) cells. Our studies indicate that SRF's interaction is critical for MRTF-A-induced promotion of both 2D and 3D cell migration, while the SAP-domain function is important selectively for 3D cell migration. Increased MRTF-A activity is associated with more effective membrane protrusion, a phenotype that is attributed predominantly to SRF's interaction of MRTF. We demonstrate formin-family protein mDia2 as an important mediator of MRTF-stimulated actin polymerization at the leading edge and cell migration. Multiplexed quantitative immunohistochemistry and transcriptome analyses of clinical BC specimens further demonstrate a positive correlation between nuclear localization of MRTF with malignant traits of cancer cells and enrichment of MRTF-SRF gene signature in pair-matched distant metastases vs primary tumors. In conclusion, this study establishes a novel mechanism of MRTF-dependent regulation of cell migration and provides evidence for the association between MRTF activity and increased malignancy in human breast cancer, justifying future development of specific small molecule inhibitors of the MRTF-SRF transcriptional complex as potential therapeutic agents in breast cancer.