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

描述（由申请人提供）：我提出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）与乳腺癌发生和发展中重要基因序列的结合。通过靶向ER¿与其同源DNA序列雌激素受体元件（estrogen receptor element， ERE）之间的结合事件，我们旨在控制乳腺癌细胞系中的基因表达，并中断乳腺癌中与癌症进展有关的基因转录。这种抑制在细胞培养中的作用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进行研究。通过检查这些化合物的活性、作用方式和特异性，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，该项目还包括在小鼠乳腺癌异种移植中非常有前景的应用，以及通过设计的聚酰胺在体内破坏ER¿-ERE结合。这项拟议的研究为癌症治疗的基因靶向全身治疗的发展做出了宝贵的贡献。

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.