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Proc Natl Acad Sci U S A. 2012 Oct 30;109(44):18060-5. doi: 10.1073/pnas.1018858109. Epub 2012 Oct 17.

Estrogen receptor prevents p53-dependent apoptosis in breast cancer.

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  • 1Center for Functional Cancer Epigenetics and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

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.

PMID:
23077249
[PubMed - indexed for MEDLINE]
PMCID:
PMC3497783
Free PMC Article
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