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| Status |
Public on Dec 04, 2014 |
| Title |
Comparison of tamoxifen and letrozole response in mammary preneoplasia of ER and aromatase over-expressing mice defines an immune-associated gene signature linked to tamoxifen resistance |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
To investigate response or resistance to endocrine therapy, mice with targeted over-expression of Esr1 or CYP19A1 to mammary epithelial cells were employed, representing two direct pathophysiological interventions in estrogen pathway signaling. Both Esr1 and CYP19A1 over-expressing mice responded to letrozole with reduced HAN prevalence and decreased mammary epithelial cell proliferation. CYP19A1 over-expressing mice were tamoxifen-sensitive but Esr1 over-expressing mice were tamoxifen-resistant. Increased ER expression occurred with tamoxifen resistance but no consistent changes in progesterone receptor, pSTAT3, pSTAT5, cyclin D1 or cyclin E levels in association with response or resistance was found. RNA-seq was employed to seek a transcriptome predictive of tamoxifen resistance using these models and a second tamoxifen-resistant model, BRCA1 deficient/Trp53 haploinsufficient mice. Sixty-eight genes associated with immune system processing were upregulated in tamoxifen-resistant Esr1 and Brca1 deficient mice whereas genes related to aromatic compound metabolic process were upregulated in tamoxifen-sensitive CYP19A1 mice. Interferon Regulatory Factor 7 was identified as a key transcription factor regulating these 68 immune processing genes. Two loci encoding novel transcripts with high homology to human IGLL1 were uniquely upregulated in the tamoxifen-resistant models. Letrozole proved to be a successful alternative to tamoxifen. Further study of transcriptional changes associated with tamoxifen resistance including immune-related genes could expand our mechanistic understanding and lead to biomarkers predictive of escape or response to endocrine therapies.
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| Overall design |
Single- and paired-end mRNA-seq with WT, Esr1 over-expressing (CERM, tetracycline-operator(tet-op)-Esr1MMTV-rtTA), CYP19A1 over-expressing (AROM, tet-op-CYP19A1MMTV-rtTA) and Brca1 KO (BRCA, Brca1fl11/fl11/MMTV-Cre/p53+/- ) mice
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| Contributor(s) |
Furth P, Kang K |
| Citation(s) |
25421723 |
| |
| Submission date |
Dec 04, 2014 |
| Last update date |
May 15, 2019 |
| Contact name |
Keunsoo Kang |
| E-mail(s) |
kangk1204@gmail.com
|
| Phone |
82-41-550-3456
|
| Organization name |
Dankook University
|
| Department |
Microbiology
|
| Lab |
Computational Biology Lab
|
| Street address |
Dandae-ro 119
|
| City |
Cheonan |
| State/province |
Chungnam |
| ZIP/Postal code |
31116 |
| Country |
South Korea |
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| Platforms (1) |
| GPL13112 |
Illumina HiSeq 2000 (Mus musculus) |
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| Samples (17)
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| Relations |
| BioProject |
PRJNA269273 |
| SRA |
SRP050547 |
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