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Cancer Discov. 2011 Sep;1(4):338-51. doi: 10.1158/2159-8290.CD-11-0101. Epub 2011 Jul 20.

ERα-dependent E2F transcription can mediate resistance to estrogen deprivation in human breast cancer.

Author information

1
Department of Cancer Biology, Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee 37232-6307, USA.

Abstract

Most estrogen receptor α (ER)-positive breast cancers initially respond to antiestrogens, but many eventually become estrogen-independent and recur. We identified an estrogen-independent role for ER and the CDK4/Rb/E2F transcriptional axis in the hormone-independent growth of breast cancer cells. ER downregulation with fulvestrant or small interfering RNA (siRNA) inhibited estrogen-independent growth. Chromatin immunoprecipitation identified ER genomic binding activity in estrogen-deprived cells and primary breast tumors treated with aromatase inhibitors. Gene expression profiling revealed an estrogen-independent, ER/E2F-directed transcriptional program. An E2F activation gene signature correlated with a lesser response to aromatase inhibitors in patients' tumors. siRNA screening showed that CDK4, an activator of E2F, is required for estrogen-independent cell growth. Long-term estrogen-deprived cells hyperactivate phosphatidylinositol 3-kinase (PI3K) independently of ER/E2F. Fulvestrant combined with the pan-PI3K inhibitor BKM120 induced regression of ER(+) xenografts. These data support further development of ER downregulators and CDK4 inhibitors, and their combination with PI3K inhibitors for treatment of antiestrogen-resistant breast cancers.

KEYWORDS:

CDK4; Estrogen receptor; aromatase inhibitor; breast; resistance

PMID:
22049316
PMCID:
PMC3204388
DOI:
10.1158/2159-8290.CD-11-0101
[Indexed for MEDLINE]
Free PMC Article

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