Abstract：
Breast cancer is a heterogeneous disease that remains the most common malignancy among women worldwide. During genomic analysis of breast tumours, mRNA levels of IQGAP3 were found to be upregulated in triple negative tumours. IQGAP3 was subsequently found to be expressed across a panel of triple negative breast cancer (TNBC) cell lines. Depleting expression levels of IQGAP3 delivered elongated cells, disrupted cell migration, and inhibited the ability of cells to form specialised invasive adhesion structures, termed invadopodia. The morphological changes induced by IQGAP3 depletion were found to be dependent on RhoA. Indeed, reduced expression of IQGAP3 disrupted RhoA activity and actomyosin contractility. Interestingly, IQGAP3 was also found to interact with p-21 activated kinase 6 (PAK6); a protein already associated with the regulation of cell morphology. Moreover, PAK6 depletion phenocopied IQGAP3 depletion in these cells. Whereas PAK6 overexpression rescued the IQGAP3 depletion phenotype. Our work points to an important PAK6-IQGAP3-RhoA pathway that drives the cellular contractility of breast cancer cells promoting both cell migration and adhesive invasion of these cells. As this phenotype is relevant to the process of metastasis and re-seeding of metastasis, the pharmacological targeting of PAK6 could lead to clinical benefit in TNBC patients.
摘要：
乳腺癌是一种异质性疾病，仍然是全球女性中最常见的恶性肿瘤。在乳腺肿瘤的基因组分析中，发现IQGAP3的mRNA水平在三阴性肿瘤中上调。随后发现IQGAP3在一组三阴性乳腺癌(TNBC)细胞系中表达。IQGAP3的表达水平下降，延长细胞，破坏的细胞迁移，并抑制细胞形成特化侵袭性粘附结构的能力，称为invadopodia。发现IQGAP3耗竭诱导的形态变化取决于RhoA。的确,IQGAP3表达降低破坏了RhoA活性和肌动球蛋白收缩性。有趣的是,还发现IQGAP3与p-21活化激酶6（PAK6）相互作用；一种已经与细胞形态调节相关的蛋白质。此外，PAK6耗竭在这些细胞中显现IQGAP3耗竭。而PAK6过表达拯救了IQGAP3耗竭表型。我们的工作指出了一个重要的PAK6-IQGAP3-RhoA途径，该途径驱动乳腺癌细胞的细胞收缩性，促进这些细胞的细胞迁移和粘附侵袭。由于这种表型与转移过程和转移的重新接种有关，PAK6的药物靶向可能导致TNBC患者的临床获益。
