Antineoplastic Efficacy of Novel Polyamine Analogues in Human Breast Cancer
Annual summary rept. 1 Jun 2004-31 May 2005
JOHNS HOPKINS UNIV BALTIMORE MD SCHOOL OF MEDICINE
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The important role of polyamine in regulation of cell growth has led to the development of a number of polyamine analogous that can intervene in natural polyamine metabolism and inhibit the growth of tumor cells. This proposal was designed to elucidate the molecular mechanisms and the therapeutic efficacy of a new generation of polyamine analogues in treatment of human breast cancer. In the second year of this award, we demonstrated that activation of p53p21 is important for the induction of polyamine analogue-induced growth inhibition and apoptosis. In our latest studies, we demonstrated that oligoamines specifically suppress the gene expression and function of the estrogen receptor alpha ERalpha, a principal determinant of breast cell growth and differentiation, leading to the subsequent down-regulation of ERalpha-target genes Simultaneous treatment with spermine could significantly reverse analogue-induced downregulation of ER expression and activity, suggesting that natural polyamines play an important role in maintaining normal ER activity. We also demonstrated that oligoamines inhibit the ERalpha promoter element, which contains the GC and CA rich boxes bound by Sp1 transcription factor family. Moreover, ERalpha has been observed to be an important mediator of the effects of the transcription factor NF-kB in response to analogue. These preliminary data indicate the possibility of a novel regulation of estrogen signaling by polyamine analogues.
- Anatomy and Physiology
- Polymer Chemistry