Inhibition of Estrogen Receptor-DNA binding with Pyrrole-Imidazole Polyamide Smal

描述（由申请人提供）：我提议的研究涉及序列特异性聚酰胺分子的开发，以抑制雌激素受体（ER）与乳腺癌起始和进展中重要的基因序列的结合。通过靶向ER <$及其同源DNA序列雌激素受体元件（ERE）之间的结合事件，我们的目标是控制乳腺癌细胞系中的基因表达，并中断乳腺癌中负责癌症进展的基因转录。将在基因特异性和全基因组mRNA表达以及细胞增殖和活力的背景下检查这种抑制在细胞培养物中的作用。通过检查这些化合物的活性，作用模式和特异性，我们相信这项研究有可能更好地了解ER介导的基因表达及其在乳腺癌中的作用。此外，该项目包括在小鼠中非常有希望地使用乳腺癌异种移植物和通过设计的聚酰胺在体内破坏ER <$-ERE结合。这项拟议的研究代表了一个有价值的贡献，为癌症治疗的基因靶向系统治疗的发展。

DESCRIPTION (provided by applicant): My proposed research involves the development of sequence-specific polyamide molecules to inhibit the binding of estrogen receptor ¿ (ER¿) to gene sequences important in the initiation and progression of breast cancer. By targeting the binding event between ER¿ and its cognate DNA sequence, the estrogen receptor element (ERE), we aim to control gene expression in breast cancer cell lines and interrupt gene transcription responsible for cancer progression in breast cancer. Effects of this inhibition in cel cultures will be examined in the context of gene-specific and genome-wide mRNA expression, as well as cell proliferation and viability. By examining the activity, mode of action, and specificity of these compounds, we believe this study has the potential to develop a better understanding of ER¿-mediated gene expression and its role in breast cancer. Furthermore, this proposed project includes a very promising use of breast cancer xenografts in mice and the disruption of ER¿-ERE binding by designed polyamides in vivo. This proposed study represents a valuable contribution to the development of gene-targeted systemic treatments for cancer therapies.