Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute at Princess Margaret Hospital, University Health Network, Toronto, ON M5G 2C1, Canada.
Proc Natl Acad Sci U S A. 2010 Feb 9;107(6):2622-7. doi: 10.1073/pnas.0914492107. Epub 2010 Jan 22.
Metastasis leads to the death of most cancer patients, and basal breast cancer is the most aggressive breast tumor type. Metastasis involves a complex cell migration process dependent on cytoskeletal remodeling such that targeting such remodeling in tumor cells could be clinically beneficial. Here we show that Hormonally Up-regulated Neu-associated Kinase (HUNK) is dramatically down-regulated in tumor samples and cell lines derived from basal breast cancers. Reconstitution of HUNK expression in basal breast cancer cell lines blocked actin polymerization and reduced cell motility, resulting in decreased metastases in two in vivo murine cancer models. Mechanistically, HUNK overexpression sustained the constitutive phosphorylation and inactivation of cofilin-1 (CFL-1), thereby blocking the incorporation of new actin monomers into actin filaments. HUNK reconstitution in basal breast cancer cell lines prevented protein phosphatase 2-A (PP2A), a phosphatase putatively acting on CFL-1, from binding to CFL-1. Our investigation of HUNK suggests that the interaction between PP2A and CFL-1 may be a target for antimetastasis therapy, particularly for basal breast cancers.
转移导致大多数癌症患者死亡，基底乳腺癌是最具侵袭性的乳腺癌类型。转移涉及依赖细胞骨架重塑的复杂细胞迁移过程，因此靶向肿瘤细胞中的这种重塑可能具有临床益处。在这里，我们表明，激素上调神经相关激酶（HUNK）在基底乳腺癌肿瘤样本和细胞系中显著下调。在基底乳腺癌细胞系中重建 HUNK 表达阻断了肌动蛋白聚合并降低了细胞迁移性，从而减少了两种体内小鼠癌症模型中的转移。从机制上讲，HUNK 过表达使 cofilin-1（CFL-1）的组成性磷酸化和失活持续存在，从而阻止新的肌动蛋白单体掺入肌动蛋白丝。在基底乳腺癌细胞系中重建 HUNK 可防止蛋白磷酸酶 2-A（PP2A）与 CFL-1 结合，PP2A 是一种推测作用于 CFL-1 的磷酸酶。我们对 HUNK 的研究表明，PP2A 和 CFL-1 之间的相互作用可能是抗转移治疗的靶点，特别是针对基底乳腺癌。
