Targeting the AP-1 Transcription Factor for the Treatment of Breast Cancer

摘要

The AP-1 transcription factor is a central component of many signal transduction pathways. We have shown that blocking AP-1 by over-expressing a dominant negative form of cJun (cjun-DN, Tam67) inhibits breast cancer cell growth. We hypothesize that inhibition of AP-1 blocks the cell cycle, suppression of AP-1 in vivo inhibits the development of breast tumors, the cjun- DN protein binds and inactivates important growth regulatory proteins present in breast cancer cells, these proteins include Jun and Fos family members as well as coactivators that bind cJun. In the present study, we demonstrated that TAM67 inhibits breast cancer growth both in vitro and in vivo. We determined the mechanism by which AP-1 blockade inhibits breast cancer growth. Our studies suggested that TAM67 inhibits breast cancer growth predominantly by inducing CDK inhibitors (such as P27), suppressing G1 cyclins expression and reducing CDKs activity, thus inducing a cell cycle block. We also showed that TAM67 binds all Jun and Fos family members, and it inhibits breast cancer cell also by interacting with cFos and preventing the recruitment of co-activators.