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A series of nitrofuran-based compounds were identified as inhibitors of estrogen signaling in a cell-based, high-throughput screen of a diverse library of small molecules. These highly related compounds were subsequently found to inhibit topoisomerase II in vitro at concentrations similar to that required for the inhibition of estrogen signaling in cells. The most potent nitrofuran discovered is ∼10-fold more active than etoposide phosphate, a topoisomerase II inhibitor in clinical use. The nitrofurans also inhibit topoisomerase I activity, with ∼20-fold less activity. Moreover, the nitrofurans, in contrast to etoposide, induce a profound cell cycle arrest in the G0-G1 phase of the cell cycle, do not induce double-stranded DNA breaks, are not substrates for multidrug resistance protein-1 export from the cell, and are amenable to synthetic development. In addition, the nitrofurans synergize with etoposide phosphate in cell killing. Clonogenic assays done on a panel of human tumors maintained ex vivo in nude mice show that the most active compound identified in the screen is selective against tumors compared with normal hematopoietic stem cells. However, this compound had only moderate activity in a mouse xenograft model. This novel class of topoisomerase II inhibitor may provide additional chemotherapeutic strategies for the development of cytotoxic agents with proven clinical utility. [Cancer Res 2007;67(9):4451–8]

The focus of this study is on the expression and regulation of the estrogen-regulated breast cancer and salivary gland expression (BASE) gene that may function as a breast cancer marker. In MCF7 cells, BASE is repressed by estrogen in an estrogen receptor α (ERα)-dependent manner. Promoter analysis of the BASE gene led to the identification of a 2-kb upstream enhancer that harbors binding sites for ERα and FoxA1. The recruitment of both ERα and FoxA1 to this region was shown by chromatin immunoprecipitation analysis. Furthermore, mutation studies and knockdown experiments show a clear separation between gene expression mediated by FoxA1 and ERα-dependent gene regulation. Additionally, we provide information on BASE expression in human breast tumor samples. [Cancer Res 2008;68(1):106–14]