P21活化激酶4（PAK4）能促进ERα阳性乳腺癌发生骨转移，乳腺癌骨转移大多造成溶骨性骨破坏，但PAK4在ERα阳性乳腺癌溶骨性骨破坏中的作用及机制尚不清楚。本项目前期筛选出PAK4新的磷酸化底物-RUNX1。已初步证实在雌激素刺激下，一方面PAK4促进RUNX1出核；另一方面PAK4促进RUNX1甲基化。两方面共同作用，解除RUNX1对靶基因Jagged1、PTHrP等的抑制作用。本课题旨在进一步确定PAK4-RUNX1信号通路在ERα阳性乳腺癌溶骨性骨转移过程中的重要生物学功能，阐明PAK4介导RUNX1的磷酸化与甲基化相互调节影响ERα阳性乳腺癌溶骨性骨转移的分子机制，确定PAK4与RUNX1相互作用与临床ERα阳性乳腺癌溶骨性骨转移的关系。旨在为临床ERα阳性乳腺癌溶骨性骨转移的治疗提供新的分子靶标。

P21-activated Kinase 4(PAK4) can promote bone metastasis of ERα-positive breast cancer, and bone metastasis of breast cancer mostly causes osteolytic bone destruction. However, the role and mechanism of PAK4 in the process of osteolytic destruction of breast cancer are not yet clear. In the early stage of this project, a new PAK4 phosphorylation substrate RUNX1 was screened out. It was preliminarily confirmed that on the one hand, PAK4 promoted RUNX1 translocation from nucleus to cytoplasm under estrogen stimulation; on the other hand, PAK4 enhanced the methylation of RUNX1. Thus, PAK4 dual roles contributed to eliminating the inhibitory effect of RUNX1 on target genes Jagged1, PTHrP, etc. This project aims to further determine the important biological functions of PAK4-RUNX1 signaling pathway in the osteolytic bone metastasis of ERα-positive breast cancer；to elucidate the molecular mechanism of PAK4-mediated RUNX1 phosphorylation and methylation in osteolytic bone metastasis of ERα-positive breast cancer and to determine the relationship between PAK4 and RUNX1 interaction and bone metastasis in clinical ERα positive breast cancer. It aims to provide new molecular targets for the treatment of osteolytic bone metastases in clinical ERα-positive breast cancer.