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| Status |
Public on Mar 02, 2018 |
| Title |
c-Jun/AP-1 overexpression reprograms ERα signaling related to tamoxifen response in ERα-positive breast cancer [ChIP-seq] |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
|
| Summary |
A critical mechanism for transcription regulation by estrogen receptor α (ER) is the tethering of ER to DNA via other transcription factors, such as AP-1. However, genome-wide assessment of the overlap in chromatin binding repertoires of these two transcription factors has not been reported. Here, we show that the AP-1 transcription factor c-Jun interacts with ER and is recruited globally to ER binding regions. Interestingly, we identify differential motif enrichment between unique ER binding regions and unique c-Jun binding regions, with FoxA1 motif enriched in both sets of binding regions, whereas GATA3 motif only specifically enriched in the unique ER binding regions but not in the unique Jun binding regions. We demonstrate that the primary mechanism for estrogen/ER-dependent transcriptional responses is the tethering of ER to DNA under conditions where it cooperates with AP-1. We provide evidence that c-Jun overexpression causes reduced sensitivity to tamoxifen in ER+ breast cancer cells. Integrated omics data reveal TGFBI as one of the most perturbed genes regulated by c-Jun. TGFBI knockdown suppresses the growth of breast cancer cells and is critical for increasing the sensitivity of tamoxifen-resistant cells to tamoxifen. We show that TGFBI expression is elevated in breast cancer than in normal breast and the basal-like tumors express high levels of TGFBI. TGFBI expression is associated with poor patient survival in ER+ breast cancer receiving endocrine therapy, highlighting a role of AP-1 via TGFBI signaling as a major determinant of endocrine response in ER+ breast tumor.
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| Overall design |
Examination of E2 and Tamoxifen induced gene expression changes in MCF-7/c-Jun -Tet cells
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| Contributor(s) |
He H, Sinha I, Fan R, Haldosén L, Yan F, Zao C, Dahlman-Wright K |
| Citation(s) |
29467493 |
| Submission date |
Aug 09, 2017 |
| Last update date |
Jul 25, 2021 |
| Contact name |
Karin Dahlman-Wright |
| Organization name |
Karolinska Institutet
|
| Department |
Department of Biosciences and Nutrition
|
| Lab |
Medicinaren 25/Neo
|
| Street address |
Blickagången 16
|
| City |
Huddinge |
| ZIP/Postal code |
14157 |
| Country |
Sweden |
| |
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| Platforms (1) |
| GPL9052 |
Illumina Genome Analyzer (Homo sapiens) |
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| Samples (7)
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| This SubSeries is part of SuperSeries: |
| GSE102412 |
ERα and AP-1 coordinate transcription and tamoxifen response in ERα-positive breast cancer |
|
| Relations |
| BioProject |
PRJNA397714 |
| SRA |
SRP115104 |
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