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PNAS 109 (44): 18060-18065

Copyright © 2012 by the National Academy of Sciences.


Estrogen receptor prevents p53-dependent apoptosis in breast cancer

Shannon T. Baileya,b,c,1, Hyunjin Shina,d,1, Thomas Westerlinga,b,c, Xiaole Shirley Liua,d, and Myles Browna,b,c,2

aCenter for Functional Cancer Epigenetics and bDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215; cDepartment of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115; and dDepartment of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, MA 02215

Edited by Kornelia Polyak, Dana-Farber Cancer Institute, Boston, MA, and accepted by the Editorial Board September 17, 2012 (received for review July 26, 2012)

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.

Key Words: cistrome • DNA damage • nuclear receptor • nutlin • doxorubicin

Author contributions: S.T.B., X.S.L., and M.B. designed research; S.T.B. performed research; S.T.B., H.S., T.W., X.S.L., and M.B. analyzed data; and S.T.B. and M.B. wrote the paper.

1S.T.B. and H.S. contributed equally to this work.

Conflict of interest statement: M.B. serves as a consultant to Novartis and receives sponsored research support from Novartis and Pfizer.

This article is a PNAS Direct Submission. K.P. is a guest editor invited by the Editorial Board.

Data deposition: The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, (accession no. GSE39870).

This article contains supporting information online at

2To whom correspondence should be addressed. E-mail: myles_brown{at}

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