Abstract
Tamoxifen (TAM) is a synthetic non-steroidal anti-estrogen compound that is widely used as an effective chemotherapeutic agent for treatment and prevention of breast cancer. Unfortunately, prolonged treatment with TAM causes TAM-responsive tumors to become TAM resistant through an as-yet-unknown mechanism. To develop novel anti-breast cancer agents that are therapeutically superior to TAM, we must first fully understand the biological effects of TAM. In this study, we found that TAM treatment of MDA-MB-361 breast cancer cells activated p21Waf1/Cip1 gene transcription independently of p53. Furthermore, TAM-induced p21Waf1/Cip1 promoter activity was enhanced by transient expression of the gene encoding Early Growth Response-1 (Egr-1) protein, a transcription factor that plays an important role in cell growth and differentiation. The TAM-induced p21Waf1/Cip1 promoter activity was blocked by the expression of small interfering RNA (siRNA) targeted to Egr-1 mRNA. In addition, induction of Egr-1 expression by TAM occurred at the transcriptional level via Ets-domain transcription factor Elk-1 through the JNK and p38 mitogen-activated protein (MAP) kinase pathways. Inhibition of the JNK and p38 MAP kinase signals inhibited Egr-1-mediated p21Waf1/Cip1 promoter activity. We conclude that TAM stimulation of p21Waf1/Cip1 gene transcription in MDA-MB-361 cells depends largely on Elk-1-mediated Egr-1 expression induced by activation of the JNK and p38 MAP kinase pathways.
Original language | English |
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Pages (from-to) | 1290-1300 |
Number of pages | 11 |
Journal | Cellular Signalling |
Volume | 19 |
Issue number | 6 |
DOIs | |
Publication status | Published - 2007 Jun |
Bibliographical note
Funding Information:This work was supported by a Grant 0620400-1 from the National Cancer Center, Korea (Y.H.L.), by a grant (M103KV010022-06K2201-02210) from Brain Research Center of the 21st Century Frontier Research Program funded by the Ministry of Science and Technology, the Republic of Korea (Y.H.L), and by grant No. R01-2006-000-10950-0(2006) from the Basic Research Program of the Korea Science and Engineering Foundation (S.Y.S.).
Keywords
- Egr-1
- Mitogen-activated protein kinase
- Tamoxifen
- p21
ASJC Scopus subject areas
- Cell Biology