|
| Status |
Public on Aug 06, 2012 |
| Title |
Interplay between AP-1 and ERalpha in regulating gene expression and proliferation networks in breast cancer cells |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
|
| Summary |
Estrogen receptor alpha (ERalpha) is a ligand-dependent transcription factor that plays an important role in breast cancer. Estrogen-dependent gene regulation by ERalpha can be mediated by interaction with other DNA-binding proteins, such as activator protein-1 (AP-1). The nature of such interactions in mediating the estrogen response in breast cancer cells remains unclear. Here we show that knockdown of c-Fos, a component of the transcription factor AP-1, attenuates the expression of 37% of all estrogen-regulated genes, suggesting that AP-1 is a fundamental factor for ERalpha-mediated transcription. Additionally, knockdown of c-Fos affected the expression of a number of genes that were not regulated by estrogen. Pathway analysis reveals that silencing of c-Fos downregulates an E2F1-dependent pro-proliferative gene network. Thus, modulation of the E2F1 pathway by c-Fos represents a novel mechanism by which c-Fos enhances breast cancer cell proliferation. Furthermore, we show that c-Fos and ERalpha can cooperate in regulating E2F1 gene expression by binding to regulatory elements in the E2F1 promoter. To start to dissect the molecular details of the cross-talk between AP-1 and estrogen signaling, we identify a novel ERalpha/AP-1 target, PKIB (cAMP-dependent protein kinase inhibitor-beta), which is overexpressed in ERalpha-positive breast cancer tissues. Knockdown of PKIB by siRNA results in drastic growth suppression of breast cancer cells. Collectively, our findings support AP-1 as a critical factor that governs estrogen-dependent gene expression and breast cancer proliferation programs.
|
| |
|
| Overall design |
MCF-7 cells were transfected with a control siRNA or with the pool of siRNAs targeting c-Fos for 72 h and were then treated with vehicle or E2 for 24 h, and global gene expression profiles were assessed. Three or four biological replicates were used for each group.
|
| |
|
| Contributor(s) |
Dahlman-Wright K, Qiao Y, Jonsson P, Williams C, Gustafsson J, Zhao C |
| Citation(s) |
22791811 |
| Submission date |
Mar 17, 2012 |
| Last update date |
Oct 11, 2016 |
| Contact name |
Chunyan Zhao |
| E-mail(s) |
chunyan.zhao@ki.se
|
| Phone |
46-8-52481126
|
| Fax |
46-8-7745538
|
| Organization name |
Karolinska Institute
|
| Department |
Biosciences and Nutrition
|
| Street address |
Hälsovägen 7-9
|
| City |
Stockholm |
| ZIP/Postal code |
SE-171 77 |
| Country |
Sweden |
| |
|
| Platforms (1) |
| GPL14550 |
Agilent-028004 SurePrint G3 Human GE 8x60K Microarray (Probe Name Version) |
|
| Samples (14)
|
|
| Relations |
| BioProject |
PRJNA153755 |
Less...
More...