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Regulation of DNA Replication Fork Genes by 17ß-Estradiol

Gene Regulation Group (E.K.L., P.L.C., C.A.A.), Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences Microarray Center (L.B., P.R.B., C.A.A.), and Biostatistics Branch (L.L.), National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709

Address all correspondence and requests for reprints to: Edward K. Lobenhofer, National Institute of Environmental Health Sciences, P.O. Box 12233 MD2-04, Research Triangle Park, North Carolina 27709. E-mail: lobenho1{at}niehs.nih.gov.

The steroid hormone estrogen can stimulate mitogenesis in hormone-responsive breast cancer epithelial cells. This action is attributed to the transcriptional activity of the ER, a ligand-dependent transcription factor. However, the exact molecular mechanism underlying estrogen-induced proliferation has yet to be completely elucidated. Using custom cDNA microarrays containing many genes implicated in cell cycle progression and DNA replication, we examined the gene expression of a hormone-responsive breast cancer cell line (MCF-7) treated with a mitogenic dose of estrogen in the absence of confounding growth factors found in serum. Gene expression changes were monitored 1, 4, 12, 24, 36, and 48 h after estrogen stimulation so that RNA levels at critical times throughout cell cycle progression could be monitored. Significant changes include the altered transcript levels of genes implicated in transcription, cellular signaling, and cell cycle checkpoints. At time points during which increased numbers of cells were progressing through S phase, a majority of the genes associated with the DNA replication fork were also found to be induced. The coexpression of DNA replication fork genes by estrogen without the support of serum growth factors indicates an important estrogen regulatory component of the molecular mechanism driving estrogen-induced mitogenesis.

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