Estrogen induced concentration dependent differential gene expression in human breast cancer (MCF7) cells: role of transcription factors.

BACKGROUND: Breast cancer cells respond to estrogen in a concentration dependent fashion, resulting in proliferation or apoptosis. The mechanism of this concentration dependent differential outcome is not well understood yet.

METHODOLOGY: Meta-analysis of the expression data of MCF7 cells treated with low (1nM) or high (100nM) dose of estradiol (E2) was performed. We identified genes differentially expressed at the low or the high dose, and examined the nature of regulatory elements in the vicinity of these genes. Specifically, we looked for the difference in the presence, abundance and spatial distribution of binding sites for estrogen receptor (ER) and selected transcription factors (TFs) in the genomic region up to 25kb upstream and downstream from the transcription start site (TSS) of these genes.

RESULTS: It was observed that at high dose E2 induced the expression of stress responsive genes, while at low dose, genes involved in cell cycle were induced. We found that the occurrence of transcription factor binding regions (TFBRs) for certain factors such as Sp1 and SREBP1 were higher on regulatory regions of genes expressed at low dose. At high concentration of E2, genes with a higher frequency of Oct-1 binding regions were predominantly involved. In addition, there were differences in the spatial distribution pattern of the TFBRs in the genomic regions among the two sets of genes.

DISCUSSION: E2 induced predominantly proliferative/metabolic response at low concentrations; but at high concentration, stress-rescue responses were induced. At high E2 concentration, classical genomic pathway involving ER binding to the regulatory regions was reduced, and alternate or indirect activation of genes through Oct-1 became more prominent.