| Abstract | Breast cancer is a growing problem in the United States and worldwide. It takes the lives of approximately 40,000 U.S. women a year. In the U.S., 1 in 8 women will develop breast cancer during the course of their lifetime and it continues to be the most commonly diagnosed cancer in women. Clearly, this is a serious issue that must be solved. Current chemotherapy treatments often result in widespread cell death, including the killing of healthy cells. Therefore, it is necessary to find alternative treatments that specifically target cancer cells. Many breast cancer cells over express estrogen receptors, which are vital to the rapid cell division and growth of tumors. Estrogen is a steroid hormone that enters the cell, binds to its receptor, translocates to the nucleus, and leads to gene expression. Previous work from our group has resulted in the development of a drug called Est-3-Melex that targets estrogen receptor-positive breast cancer. The drug contains a DNA methylating group (Melex) conjugated to estrogen. The drug acts by the binding of the estrogen portion of the molecule to its receptor that ultimately translocates to the nucleus. While in the nucleus, the Melex portion of the compound is brought in close proximity to the DNA and methylates the adenine base, eventually resulting in cell death. Essentially, this is a receptor targeted cancer therapy. In order to test the toxicity of this drug, we utilized a MTT cytotoxicity assay, which quantifies the amount of cell death. Est-3-Melex was more toxic to cancer cells that overexpressed the estrogen receptor compared to those that did not. Treating the estrogen receptor positive breast cancer cells with excess amounts of estrogen inhibited Est-3-Melex-induced cell death. Fluorescence imaging was also utilized to visualize localization of the drug. A fluorescent tag was attached to Est-3-Melex and introduced into estrogen receptor-positive breast cancer cells. The results showed the drug localized to the nucleus and this localization was inhibited by estrogen. Our results suggest that Est-3-Melex is effective in specifically killing estrogen receptor positive breast cancer cells by binding to the estrogen receptor. Additional investigations are underway to identify the mechanism of cell death. |
