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 ...

The transcription factor Egr1 is a direct regulator of multiple tumor suppressors including TGFβ1, PTEN, p53, and fibronectin

“…24 RT-PCR experiments performed on human thyroid tumors showed that the absence of Egr1 mRNA is always paralleled by the absence of PTEN mRNA, suggesting that Egr1-dependent mechanisms may play a role in the absence of PTEN gene expression that occurs during thyroid cell transformation. 24 Egr1 protein levels are suppressed or absent in a variety of human tumor cell lines 13,28 and tumors, including breast carcinoma, 28 glioblastoma, 14,15 lung cancer, 29,30 and lymphoma. 31 Moreover, in the case of human nonsmall-cell lung cancer, Ferraro et al 32 examined an extensive series of samples from over 125 patients and observed that Egr1 expression predicts both PTEN level and survival to a high degree of significance.…”

“…14 The observations indicate that Egr1 expression is commonly suppressed in tumors as has been observed in cells lines. 13,28 Paradoxically, increased expression of Egr1 is consistently observed in prostate cancer where growing evidence indicates that Egr1 is oncogenic. Russell and co-workers 55 observed that Egr1 mRNA levels were elevated in 12 of 12 cases of organ-confined prostate cancer but not in breast or ovarian cancers, or in rapidly dividing rat ventral prostate cells.…”

Sphingosine‐1‐phosphate receptor type 1 regulates glioma cell proliferation and correlates with patient survival

“…S1P 1 receptor signaling negatively controls cell proliferation either by knockdown or by overexpression of the S1P 1 receptor in glioma cell lines. Furthermore, expression of the S1P 1 receptor correlated with that of early growth response-1 (Egr-1), which is an essential transcriptional factor considered to be a central regulator in tumor cell proliferation [20][21][22][23][24] through phosphatase and tensin homologue deleted in chromosome 10 (PTEN) in glioblastoma. These results suggest that S1P 1 receptor signaling plays an important role in the malignant behavior of human glioma.…”

Review Paper: Cancer Chemopreventive Compounds and Canine Cancer

“…A number of reports indicate that EGR-1 acts as a tumor suppressor gene. EGR-1 is downregulated in tumors and an array of tumor cell lines 36 and is induced by several tumor suppressor proteins. 82,85 We also have identified EGR-1 as another NSAID-induced gene.…”