RecQL4是解旋酶家族中的一员，其编码区突变导致的基因功能的缺失可引起人类早衰以及肿瘤高发，RecQL4通过参与不同的DNA修复途径而在维持基因组稳定性方面起重要作用。我们的前期结果发现，在乳腺肿瘤细胞株中，染色体8q24区域拷贝数的增加可导致RecQL4在乳腺肿瘤细胞中的高表达；同时利用实时定量RT-PCR的方法证实:88.4%(38/43)的临床原发乳腺肿瘤其RecQL4 mRNA水平升高3倍以上；然而，RecQL4高表达是否与乳腺肿瘤的进展相关，目前还不清楚。本项目将搜集不同类型的临床乳腺肿瘤标本，检测其RecQL4 mRNA和蛋白水平的变化，并与临床病理指标相关联；同时利用免疫共沉淀结合蛋白质谱的方法寻找RecQL4的互作蛋白网络，并建立RecQL4在乳腺组织中特异高表达的小鼠模型，本研究目的是利用细胞及动物模型阐明RecQL4高表达促进乳腺肿瘤进展的分子机制。

RecQL4 belongs to a family of RecQ helicase with DNA-unwinding activity. Loss of protein function due to gene mutations has been linked to a subset of human disorder- Rothmund-Thomson syndrome (RTS) characterized by premature aging and cancer predisposition. RecQL4 plays an important role in maintaining genome stability through participating in various DNA repair pathways. Based on our preliminary data in breast cancer cell lines, gain of 8q24, the chromosome region RecQL4 is mapped to, and subsequent overexpression of RecQL4 were observed in these lines. We further provided the prelimianry data showing that mRNA level of RecQL4 was increased over 3-fold in 88.4%(38/43) primary breast tumor samples examined when compared to normal breast tissues. However, it is not clear whether or not RecQL4 overexpression correlates with breast tumor progressoin. In this proposal,we will examine the RecQL4 mRNA and protein levels in primary breast tumor samples with different histological types, and the result will be used for correlating with their pathological parameters.The interacting protein network of RecQL4 that mediates the RecQL4 effect will be identified by the approaches of Co-IP plus LC-MS (Liquid chromatography-mass spectrometry)analysis. Meanwhile,RecQL4 knock-in mouse model with specific oeverexpression of RecQL4 in mammary tissues will be used to study the in vivo breast tumor progression related to RecQL4 overexpression. The overall aim of this application is to use the in vitro cell and in vivo animal models to define the molecular mechanism(s) of RecQL4 overexpression in promoting human breast tumor progression.