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

描述(申请人提供)：我建议的研究涉及开发序列特定的聚酰胺分子，以抑制雌激素受体(ER)与乳腺癌发生和发展中重要的基因序列的结合。通过针对ER与其同源DNA序列--雌激素受体元件(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，并阻断与乳腺癌进展有关的基因转录。这种抑制在细胞培养中的影响将在基因特异性和基因组范围的mRNA表达以及细胞增殖和活力的背景下进行检验。通过检测这些化合物的活性、作用方式和特异性，我们相信这项研究有可能更好地理解ER介导的基因表达及其在乳腺癌中的作用。此外，这项拟议的项目包括非常有前景的用于小鼠的乳腺癌异种移植，以及通过设计的聚酰胺在体内破坏ER？-ere结合。这项拟议的研究对癌症治疗的基因靶向系统治疗的发展做出了有价值的贡献。

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.