Estrogen receptor prevents p53-dependent apoptosis in breast cancer
Open Access
- 17 October 2012
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 109 (44), 18060-18065
- https://doi.org/10.1073/pnas.1018858109
Abstract
More than two-thirds of breast cancers express the estrogen receptor (ER) and depend on estrogen for growth and survival. Therapies targeting ER function, including aromatase inhibitors that block the production of estrogens and ER antagonists that alter ER transcriptional activity, play a central role in the treatment of ER+ breast cancers of all stages. In contrast to ER− breast cancers, which frequently harbor mutations in the p53 tumor suppressor, ER+ breast cancers are predominantly wild type for p53. Despite harboring wild-type p53, ER+ breast cancer cells are resistant to chemotherapy-induced apoptosis in the presence of estrogen. Using genome-wide approaches, we have addressed the mechanism by which ER antagonizes the proapoptotic function of p53. Interestingly, both ER agonists such as estradiol and the selective ER modulator (SERM) tamoxifen promote p53 antagonism. In contrast, the full ER antagonist fulvestrant blocks the ability of ER to inhibit p53-mediated cell death. This inhibition works through a mechanism involving the modulation of a subset of p53 and ER target genes that can predict the relapse-free survival of patients with ER+ breast cancer. These findings suggest an improved strategy for the treatment of ER+ breast cancer using antagonists that completely block ER action together with drugs that activate p53-mediated cell death.Keywords
This publication has 59 references indexed in Scilit:
- A Genomic Predictor of Response and Survival Following Taxane-Anthracycline Chemotherapy for Invasive Breast CancerJama-Journal Of The American Medical Association, 2011
- FOXA1 is a key determinant of estrogen receptor function and endocrine responseNature Genetics, 2010
- An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1,809 patientsBreast Cancer Research and Treatment, 2009
- ChIP-Seq of ERα and RNA polymerase II defines genes differentially responding to ligandsThe EMBO Journal, 2009
- Estradiol downregulation of the tumor suppressor gene BTG2 requires estrogen receptor‐α and the REA corepressorInternational Journal of Cancer, 2009
- Systematic and integrative analysis of large gene lists using DAVID bioinformatics resourcesNature Protocols, 2008
- FoxA1 Translates Epigenetic Signatures into Enhancer-Driven Lineage-Specific TranscriptionCell, 2008
- Genome-wide analysis of estrogen receptor binding sitesNature Genetics, 2006
- Chromosome-Wide Mapping of Estrogen Receptor Binding Reveals Long-Range Regulation Requiring the Forkhead Protein FoxA1Cell, 2005
- Endocrine-responsive breast cancer and strategies for combating resistanceNature Reviews Cancer, 2002