title: ERα-dependent E2F transcription can mediate resistance to estrogen deprivation in human breast cancer.
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.
authors: Department of Cancer Biology, Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee 37232-6307, USA.
authors: Todd W
authors: TW
authors: Miller
authors: Justin M
authors: JM
authors: Balko
authors: Emily M
authors: EM
authors: Fox
authors: Zara
authors: Z
authors: Ghazoui
authors: Anita
authors: A
authors: Dunbier
authors: Helen
authors: H
authors: Anderson
authors: Mitch
authors: M
authors: Dowsett
authors: Aixiang
authors: A
authors: Jiang
authors: R Adam
authors: RA
authors: Smith
authors: Sauveur-Michel
authors: SM
authors: Maira
authors: H Charles
authors: HC
authors: Manning
authors: Ana M
authors: AM
authors: González-Angulo
authors: Gordon B
authors: GB
authors: Mills
authors: Catherine
authors: C
authors: Higham
authors: Siprachanh
authors: S
authors: Chanthaphaychith
authors: Maria G
authors: MG
authors: Kuba
authors: William R
authors: WR
authors: Miller
authors: Yu
authors: Y
authors: Shyr
authors: Carlos L
authors: CL
authors: Arteaga
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D045744:Cell Line, Tumor; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D050684:E2F Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D020847:Estrogen Receptor Modulators / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism*; D004967:Estrogens / Q000172:deficiency* / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D050684:E2F Transcription Factors; D020847:Estrogen Receptor Modulators; D047628:Estrogen Receptor alpha; D004967:Estrogens; D019869:Phosphatidylinositol 3-Kinases; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4