Role of Stat-3 in ER- Breast Tumors.

摘要

This application proposed to test two hypotheses. The first hypothesis to be tested in this was whether c-myb and A-myb genes regulate ductal cell proliferation and whether abnormalities in the expression of these genes results in breast cancer. Our studies employed both in vitro and in vivo systems. During the first phase of the granting period, we developed embryonic stem cells to generate mice that either have breast-specific deletion of c-myb gene or breast-specific truncation of c-myb gene leading to its activation. In addition, we developed in vitro systems to test the oncogenic behavior of c-myb and A-myb genes. These results show that over-expression of c-myb or A-myb leads to the transformation of breast epithelial cells validating our hypothesis that these two genes constitute excellent targets for drug development. Analysis of human breast tumor cell lines showed that c-myb is expressed in a majority of ER+ human breast carcinomas, while A-myb expression is seen predominantly in ER- cell lines. Our results also show that blockage of the biochemical function of c-myb results in a complete block to ER+ breast tumor cell proliferation. The second hypothesis we tested was whether STAT family of transcription factors play a role in the development of ER-negative breast carcinomas. For this, we have examined the activation status of two STATs, STAT-3 and STAT-5. Our results show that several of the ER-negative breast carcinomas express constitutively activated Src kinases, which mediate the phosphorylation of STAT-3, which in turn could mediate their proliferative function and oncogenicity. The constitutively activated status of STAT-3, therefore serves as a good diagnostic marker for the detection of ER-negative breast carcinoma development.