Antineoplastic Efficacy of Novel Polyamine Analogues in Human Breast Cancer
Annual summary rept. 1 Jun 2005-31 May 2006
JOHNS HOPKINS UNIV BALTIMORE MD SCHOOL OF MEDICINE
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The critical role of polyamines in cell growth has led to the development of a number of agents that interfere with polyamine metabolism including a novel class of polyamine analogues, oligoamines. This proposal was designed to elucidate the molecular mechanisms and the therapeutic efficacy of oligoamines in treatment of human breast cancer. In the third year of this award, we demonstrated that oligoamines specifically suppress the expression of estrogen receptor ER and its target genes. Further analysis demonstrated that oligoamines disrupted the DNA binding activity of Sp1 transcription factors to an ER minimal promoter element containing GCCA rich boxes. Treatment of tumor cells with the JNK specific inhibitor SP600125, or expression of the c-Jun dominant negative inhibitor, TAM67, blocked the oligoamineactivated JNKc-Jun pathway and enhanced oligoamine-inhibited ER expression, suggesting that AP-1 is a positive regulator of ER expression and that oligoamine activated JNKAP-1 activity may antagonize the down-regulation of ER induced by oligoamines. These results suggest a novel antiestrogenic mechanism for specific polyamine analogues in human breast cancer cells.
- Medicine and Medical Research