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

Miller TW, Balko JM, Fox EM, Ghazoui Z, Dunbier A, Anderson H, Dowsett M, Jiang A, Smith RA, Maira SM, Manning HC, González-Angulo AM, Mills GB, Higham C, Chanthaphaychith S, Kuba MG, Miller WR, Shyr Y, Arteaga CL
Cancer Discov. 2011 1 (4): 338-51

PMID: 22049316 · PMCID: PMC3204388 · DOI:10.1158/2159-8290.CD-11-0101

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.

©2011 AACR.

MeSH Terms (17)

Animals Breast Neoplasms Cell Line, Tumor Cyclin-Dependent Kinase 4 Down-Regulation Drug Resistance, Neoplasm E2F Transcription Factors Estrogen Receptor alpha Estrogen Receptor Modulators Estrogens Female Gene Expression Humans Mice Mice, Nude Phosphatidylinositol 3-Kinases Transcription, Genetic

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