|
| Status |
Public on Jan 13, 2017 |
| Title |
Genomic pathways modulated by Twist in breast cancer |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
|
| Summary |
Background: The basic helix-loop-helix transcription factor TWIST1 (Twist) is involved in embryonic cell lineage determination and mesodermal differentiation. There is evidence to indicate that Twist expression plays a role in breast tumor formation and metastasis, but the role of Twist in dysregulating pathways that drive the metastatic cascade is unclear. Importantly, the genes and pathways dysregulated by Twist in cell lines and mouse models have not been validated against data obtained from patient samples.
Methods: We over-expressed the human Twist gene in non-metastatic MCF-7 breast cancer cells to generate the estrogen-independent metastatic breast cancer cell line MCF-7/Twist. These cells were then inoculated in the mammary fat pad of female severe compromised immunodeficient mice, which subsequently formed xenograft tumors that metastasized to the lungs. Microarray data was collected from both in vitro (MCF-7 and MCF-7/Twist cell lines) and in vivo (primary tumors and lung metastases) models of Twist expression. Our data was compared to publically available gene signatures of different subtypes, classes, and grades of human breast cancers.
Results: Our data establishes a Twist over-expressing mouse model of breast cancer, which metastasizes to the lung and replicates some of the ontogeny of human breast cancer progression. Gene profiling data, following Twist expression, exhibited novel metastasis driver genes as well as cellular maintenance genes that were synonymous with the metastatic process. We demonstrated that the genes and pathways altered in the transgenic cell line and metastatic animal models generated, parallel many of dysregulated gene pathways observed in human breast cancers.
Conclusions: Analogous gene expression patterns observed in both in vitro and in vivo Twist preclinical models of breast cancer metastasis and public patient data sets supports the functional role of Twist in promoting breast tumor metastasis. Our data indicates that genetic dysregulation of Twist at the cellular level drives alterations in related gene pathways in the Twist metastatic mouse model which are comparable to changes seen in breast cancer patient samples. Lastly, we have identified novel genes and pathways that could be further investigated as targets for drugs to ultimately treat metastatic breast cancer.
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| Overall design |
Samples were selected from all stages of the metastatic cascade in both cell culture and in the resulting metastatic mouse model of breast cancer. RNA was extracted from the MCF-7 cell line (2 replicates), MCF-7/Twist cell line (2 replicates), cells cultured from MCF-7/Twist primary tumors in mice (2 replicates), and cells cultured from MCF-7/Twist lung metastases (4 replicates).
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| Contributor(s) |
Vesuna F, Raman V |
| Citation(s) |
28086829 |
| NIH grant(s) |
| Grant ID |
Grant title |
Affiliation |
Name |
| R01 CA131250 |
The role of Twist in inducing breast cancer initiating cells and metastasis |
JOHNS HOPKINS UNIVERSITY |
RAMAN |
| R01 CA140226 |
Functional Imaging of Twist induced breast cancer |
JOHNS HOPKINS UNIVERSITY |
RAMAN |
|
| Submission date |
Oct 06, 2016 |
| Last update date |
Mar 25, 2019 |
| Contact name |
Venu Raman |
| E-mail(s) |
vraman2@jhmi.edu
|
| Organization name |
Johns Hopkins University
|
| Department |
Radiology
|
| Street address |
720 Rutland Ave, Traylor 338
|
| City |
Baltimore |
| State/province |
Maryland |
| ZIP/Postal code |
21205 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL570 |
[HG-U133_Plus_2] Affymetrix Human Genome U133 Plus 2.0 Array |
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| Samples (11)
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| Relations |
| BioProject |
PRJNA345609 |
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