PAK4在ER-α阳性乳腺癌转移中的作用及机制

ER-α阳性乳腺癌能发生转移，但机制尚不清楚。PAK4是我们发现的ER-α新的互作蛋白，在乳腺癌组织中高表达并与ER-α蛋白在细胞核内共定位。已初步证实PAK4与ER-α发生相互作用，并与MTA1结合, 形成新的复合物，调节ER-α转录功能，可能在乳腺癌EMT及转移中起重要作用。 本课题旨在验证PAK4与ER-α及MTA1等在乳腺癌细胞内发生功能性结合，形成新的转录复合物，研究该复合物调控Slug、E-cadherin和乳腺癌EMT及转移的分子机制，利用裸鼠实验证实PAK4与ER-α相互作用对乳腺癌侵袭转移的影响，应用临床乳腺癌组织验证PAK4表达与ER-α、E-cadherin表达的关系及与临床ER-α阳性乳腺癌转移和预后的关系。本研究使我们弄清信号分子PAK4与ER-α相互作用在乳腺癌EMT及转移中的作用及其机制，为临床ER-α阳性乳腺癌分子分型及治疗提供新的分子标记及治疗靶点。

Estrogen receptor-α (ER-α) positive breast cancer can metastasize, but the mechanism involved remains largely unknown. We found that PAK4 is a novel ER-α binging protein and interacts with MTA1. Overexpressed PAK4 colocalized with ER-α in the nucleus of breast cancer tissues. As a component of novel complex, PAK4 regulated ER-α transactivation and may play an important role in the EMT and metastasis of ER-α positive breast cancer. In this project, we aim to confirm the interaction of PAK4 with ER-α and MTA1 and the formation of this novel complex and to explore the molecular mechanism for this transcriptional complex regulating Slug, E-cadherin, EMT and metastasis in breast cancer cells. We plan to confirm that PAK4 interaction with ER-α affect the invasion and metastasis in a xenograft mouse model and find out the correlation of PAK4 expression with ER-α and E-cadherin expression in clinical breast cancer tissues and finally we want to know the correlation of PAK4 expression with metastasis and prognosis in ER-α positive breast cancer. This project will make us understanding of the mechanistic role of PAK4 interaction with ER-α in EMT and metastasis of breast cancer, providing a novel molecular marker and therapeutic target for ER-α positive breast cancer patients with poor clinical outcome.