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- W2000377706 abstract "CTRC-AACR San Antonio Breast Cancer Symposium: 2008 AbstractsAbstract #4065 p53 is a tumor suppressor frequently inactivated in cancers. Mdm2 targets p53 for proteasomal degradation via E3 ubiquitin ligase activity and represses p53 transcriptional activity by co-localization with p53 on the chromatin. Mdm2 overexpression is associated with estrogen signaling in breast cancer. To investigate estrogen-associated tumorigenesis and p53 pathway suppression, we examined estrogen receptor positive and p53 wild-type breast cancer cell lines, MCF-7 and ZR-75-1. MCF-7 cells are heterozygous for the mdm2 gene single nucleotide polymorphism from T to G at position 309 (SNP309 T/G) and ZR-75-1 are SNP309 homozygous T/T. Cells that carry the G-allele overexpress Mdm2. We found that in the presence of estrogen, the transcriptional activity of p53 in MCF-7, but not in ZR-75-1 cells, was selectively compromised. When MCF-7 cells were treated with the DNA-damaging drug etoposide or the Mdm2 antagonist Nutlin-3, transcription of p53 target genes p21, mdm2, puma and gadd45 was upregulated. However in the presence of estrogen, transcription of puma and gadd45, and not of mdm2 or p21, was downregulated. In ZR-75-1 cells, we did not observe selective inhibition of p53 transcriptional activity in the presence of estrogen. Importantly, we could potentiate p53 transcriptional activity by adding mdm2 siRNA in the presence of estrogen. The coordination between suppression of p53 transcriptional activity and mdm2 SNP309 genotype suggests that estrogen downregulates the p53 response in breast cancer cells by selecting for cells that overexpress Mdm2. This suggests that downregulating Mdm2 in ER+ breast cancer cells could be a beneficial therapeutic approach. This work was supported by The Breast Cancer Research Foundation and was facilitated by grant number RR-03037 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH).Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4065." @default.
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- W2000377706 date "2009-01-15" @default.
- W2000377706 modified "2023-09-25" @default.
- W2000377706 title "p53 transcriptional activity is selectively suppressed by estrogen in SNP309 mdm2 overexpressing breast cancer cells." @default.
- W2000377706 doi "https://doi.org/10.1158/0008-5472.sabcs-4065" @default.
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