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

TW Miller, JM Balko, EM Fox, Z Ghazoui, A Dunbier… - Cancer discovery, 2011 - AACR
TW Miller, JM Balko, EM Fox, Z Ghazoui, A Dunbier, H Anderson, M Dowsett, A Jiang
Cancer discovery, 2011AACR
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 …
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.
Significance: ERα retains genomic activity and drives a CDK4/E2F-dependent transcriptional program despite estrogen deprivation therapy. Combined inhibition of ER and PI3K induced regression of ER+ xenografts, supporting further development of strong ER downregulators and CDK4 inhibitors, and their combination with PI3K inhibitors for the treatment of antiestrogen-resistant breast cancers. Cancer Discovery; 1(4); 338–51. ©2011 AACR.
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