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ERα-dependent E2F transcription can mediate resistance to estrogen deprivation in human breast cancer.
- Source :
-
Cancer discovery [Cancer Discov] 2011 Sep; Vol. 1 (4), pp. 338-51. Date of Electronic Publication: 2011 Jul 20. - Publication Year :
- 2011
-
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.<br /> (©2011 AACR.)
- Subjects :
- Animals
Breast Neoplasms metabolism
Breast Neoplasms therapy
Cell Line, Tumor
Cyclin-Dependent Kinase 4 genetics
Cyclin-Dependent Kinase 4 metabolism
Down-Regulation
Drug Resistance, Neoplasm
Estrogen Receptor Modulators pharmacology
Estrogens metabolism
Estrogens pharmacology
Female
Gene Expression
Humans
Mice
Mice, Nude
Phosphatidylinositol 3-Kinases genetics
Phosphatidylinositol 3-Kinases metabolism
Transcription, Genetic
Breast Neoplasms genetics
E2F Transcription Factors genetics
E2F Transcription Factors metabolism
Estrogen Receptor alpha genetics
Estrogen Receptor alpha metabolism
Estrogens deficiency
Subjects
Details
- Language :
- English
- ISSN :
- 2159-8290
- Volume :
- 1
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Cancer discovery
- Publication Type :
- Academic Journal
- Accession number :
- 22049316
- Full Text :
- https://doi.org/10.1158/2159-8290.CD-11-0101