Decreased Egr-1 expression in human, mouse and rat mammary cells and tissues correlates with tumor formation

Abstract

We have examined several types of tumor cell lines and shown that they invariably expressed little or no Egr-1, in contrast to their normal counterparts. We have previously shown that the expression of exogenous Egr-1 in human breast and other tumor cells markedly reduces transformed growth and tumorigenicity. We therefore hypothesized that the loss of Egr-1 expression plays a role in transformation. All human and mouse breast cancer cell lines and tumors examined had reduced Egr-1 expression compared with their normal counterparts. Reduced Egr-1 expression was also observed in 7,12-dimethylbenz(a)anthracene (DMBA)-induced rat mammary tumors, and this level increased to normal levels in tumors that regressed after tamoxifen treatment. We concluded, therefore, that loss of Egr-1 expression may play a role in the deregulation of normal growth in the tumorigenic process and that Egr-1 acts as a tumor suppressor gene. The early growth response gene, Egr-1 (Sukhatme et al., 1988) (zfp-6 in Standardized Genetic Nomenclature for Mice), also known as NGF1A, Krox 24, zif268 and T1S-8, encodes a protein with 3 adjacent zinc-finger motifs, structures that are present in many DNA-binding transcription factors. The Egr family of proteins consists of 4 members that all bind to the same DNA element: GCGGGGGCG or GCGT/GGGGCG (Christy and Nathans, 1989;LeMaire et al., 1988) because of the remarkable conservation of their zinc-finger DNA binding domains. The Egr family is a highly evolutionarily conserved set of genes but it has proved difficult to define a precise role. One member of the family, WT1, has a homologous zinc-finger domain with 4 fingers that bind to the same DNA motif. WT1 has been categorized as a tumor suppressor gene that is mutant in Wilms' tumor disease in children (Rauscher, 1993).We have shown that Egr-1 has tumor suppressor properties and that the DNA-binding domain is necessary for this activity (Huang et al., 1994a;. The over-expression of Egr-1 in transformed cells suppressed their growth in soft agar and their growth as tumors in athymic mice. In contrast, further inhibition of Egr-1 in mouse transformed cells using antisense-expression vectors increased the transformed character of the cells (Huang et al., 1994b). During the analysis of a range of tumor cell lines, we observed that the expression of Egr-1 was often anomalously low. We have shown that the over-expression of Egr-1 can restore normal growth patterns to these tumor cells, which suggested that the loss of this transcription factor might be either a cause of, or may accompany, the loss of growth control leading to tumor production. Some of this growth down-regulation is due to the induction of Transforming Growth Factor-b expression (Liu et al., 1996). This factor is a growth inhibitor of epithelial cells that express the receptor and accounts for reduced growth rates in some cell types.We have examined here the expression of Egr-1 in human breast tissues and mammary cell lines and tissues. The data strongly support the hypothesis that Egr-1...

Redox State, Oxidative Stress, and Molecular Mechanisms of Protective and Toxic Effects of Bilirubin on Cells

“…Egr-1 is involved in the regulation of cell growth in response to extracellular signals, such as mitogens and growth factors, as well as during the cellular response to oxidative stress [92,93]. Studies of gene expression in human tumor cells and tissues indicate that Egr-1 exhibits prominent tumor suppressor functions [94]. This is mediated by upregulation of the expression of target genes that lead to apoptosis and inhibition of cell proliferation, such as p53 and the Phosphatase and Tensin homolog, (PTEN) [95].…”

GPER mediates the Egr-1 expression induced by 17β-estradiol and 4-hydroxitamoxifen in breast and endometrial cancer cells

“…Egr-1 promotes cell proliferation, differentiation, and transformation [13], however, it may also play a role in apoptosis and in the suppression of tumor growth [14,15]. The exposure to estrogens was shown to induce Egr-1 expression in rodent uterus [16,17] and in human breast cancer cells [18,19].…”

APE1/Ref-1 regulates PTEN expression mediated by Egr-1

“…Egr-1 is involved in the regulation of cell proliferation in response to extracellular signal such as mitogens and growth factors, as well as oxidative stress [12,13]. Studies of gene expression in human tumour cells and tissues support Egr-1's function as a tumour suppressor [14,15]. Egr-1 regulates expression of many genes such as p53 and the phosphoinositol phosphatase and tensin homologue (PTEN) that control cell-growth arrest and apoptosis [16,17].…”