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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Oct 03, 2018 |
| Title |
Targeting 17q23 amplicon to overcome the resistance to anti-HER2 therapy in HER2+ breast cancer |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Amplification of chromosome 17q23 is a frequent genomic event that occurs in ~ 11% of human breast cancers. The 17q23 amplification is enriched in HER2+ breast cancers, which is significantly correlated with poor clinical outcomes. Previous studies have identified the oncogenic phosphatase WIP1 gene in the amplicon, which functions as a master inhibitor in DNA damage response. While the possibility of any other protein-coding oncogenes in the WIP1-containing 17q23 amplicon was ruled out, our analysis of human breast cancer genomics uncovered an oncogenic microRNA gene, MIR21, in a majority of the WIP1-containing amplicons. Interestingly, DEAD-box helicase 5 (DDX5), co-amplified with WIP1 and MIR21 in the 17q23 amplicon, facilitates the essential processing of primary miR-21 transcripts. Accordingly, the 17q23 amplification results in aberrant expression of WIP1 and miR-21, which not only promotes breast tumorigenesis, but also leads to resistance to anti-HER2 therapies. Inhibiting WIP1 and miR-21 using small molecular inhibitor against WIP1 (GSK2830371) and anti-miR-21 oligonucleotides selectively inhibits the proliferation, survival and tumorigenic potential of HER2+ breast cancer cells harboring 17q23 amplification. However, the in vivo bioavailability of the two agents in their free form is poor. To overcome the resistance of trastuzumab-based therapies in vivo, we developed pH-sensitive nanoparticles for specific co-delivery of the two agents into breast tumors. The nanoparticles consist of four materials approved by the Food and Drug Administration (FDA) for medical use: Poly (d,l-lactide-co-glycolide) (PLGA), Pluronic F127 (PF127), chitosan, and 1,2-dipalmitoyl-sn-glycerol-3-phosphocholine (DPPC). Moreover, chitosan was modified with guanidine to form chitosan-guanidine (CG), which not only can improve the encapsulation efficiency of anti-miR-21 oligonucleotides but also effectively capture carbon dioxide (CO2) into the nanoparticle to achieve the ‘nano-bomb’ effect for triggered drug release under the reduced pH in tumors. The two agents (inhibitors of miR-21 and WIP1)-laden nanoparticles can be used to efficiently kill trastuzumab-resistant HER2+ breast cancer cells, leading to a profound reduction of the tumor growth in vivo. These results demonstrate the great potential of the combined treatment of WIP1 and miR-21 inhibitors for the HER2+ breast cancers resistant to anti-HER2-based therapies.
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| Overall design |
Primary MMTV-ErbB2 mouse mammary epithelial cells (8-wk old) were isolated as previously reported and then total mRNA was extracted using Direct-zol RNA extraction kit (duplicates, Zymo Research) and then submitted for deep sequencing. Deep sequence data were mapped, normalized and the differentially expressed genes were collected for pathway analysis.
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| Contributor(s) |
Liu Y, Xu J, Choi HH, Han C, Fang Y, Li Y, Van der Jeught K, Xu H, Zhang L, Frieden M, Wang L, Eyvani H, Sun Y, Zhao G, Zhang Y, Liu S, Wan J, Huang C, Ji G, Lu X, He X, Zhang X |
| Citation(s) |
30413718 |
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| Submission date |
Aug 29, 2018 |
| Last update date |
Mar 19, 2019 |
| Contact name |
Xiongbin Lu |
| E-mail(s) |
xiolu@iu.edu
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| Phone |
(317) 274-4398
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| Organization name |
Indiana University School of Medicine
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| Street address |
980 W. Walnut Street, R3-C218D MMGE
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| City |
Indianapolis |
| State/province |
Indiana |
| ZIP/Postal code |
46202 |
| Country |
USA |
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| Platforms (1) |
| GPL21103 |
Illumina HiSeq 4000 (Mus musculus) |
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| Samples (2) |
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| Relations |
| BioProject |
PRJNA488470 |
| SRA |
SRP159101 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE119210_RAW.tar |
14.2 Mb |
(http)(custom) |
TAR (of TXT) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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