ER alpha-Dependent E2F Transcription Can Mediate Resistance to Estrogen Deprivation in Human Breast Cancer

作者：Miller Todd W; Balko Justin M; Fox Emily M; Ghazoui Zara; Dunbier Anita; Anderson Helen; Dowsett Mitch; Jiang Aixiang; Smith R Adam; Maira Sauveur Michel; Manning H Charles; Gonzalez Angulo Ana M; Mills Gordon B; Higham Catherine; Chanthaphaychith Siprachanh; Kuba Maria G; Miller William R; Shyr Yu; Arteaga Carlos L^*

来源：Cancer Discovery, 2011, 1(4): 338-351.

DOI：10.1158/2159-8290.CD-11-0101

Most estrogen receptor a (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: ER alpha 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.

• 出版日期2011-9