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.
Over half of all breast cancers overexpress estrogen receptor ? (ER?) and the presence of elevated levels of ER? is linked to an increased risk of breast cancer. This proposal describes the design and synthesis of small molecule inhibitors known as polyamides to disrupt ER? from binding to specific sequences of DNA. This work intends to inhibit ER?-activated gene expression in breast cancer cell lines and animal models of breast cancer.
|Xu, Liang; Wang, Wei; Gotte, Deanna et al. (2016) RNA polymerase II senses obstruction in the DNA minor groove via a conserved sensor motif. Proc Natl Acad Sci U S A 113:12426-12431|
|Hargrove, Amanda E; Martinez, Thomas F; Hare, Alissa A et al. (2015) Tumor Repression of VCaP Xenografts by a Pyrrole-Imidazole Polyamide. PLoS One 10:e0143161|