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Targeting the AP-1 Transcription Factor for the Treatment of Breast Cancer
Annual rept. 24 Sep 2001-23 Sep 2002
BAYLOR COLL OF MEDICINE HOUSTON TX
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The AP-l transcription factor is a central component of many signal transduction pathways. We have shown that blocking AP-l by over-expressing a dominant negative form - of cJun cjun-DN, Tam67 inhibits breast cancer cell growth. We hypothesize that- inhibition of AP-l blocks the cell cycle, reverses TAM-resistance of breast cancer cells, and suppression of AP-l in vivo causes regression of existing breast tumors. 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-l blockade inhibits breast cancer growth. Our studies suggested that TAM67 inhibits breast cancer growth predominantly by inducing CDK inhibitors such as P27, suppressing GI cyclins expression and reducing CDKs activity, thus inducing a cell cycle block. We also showed that TAM67 induces apoptosis in serum-free condition in breast cancer cells. We are currently investigating the molecular mechanism by which TAM67 causes a cell cycle block. Over the next year we will investigate whether inhibition of AP-l activity reverses tamoxifen-resistance of
APPROVED FOR PUBLIC RELEASE