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| Status |
Public on Dec 05, 2011 |
| Title |
Transcriptional profiling of MMTV-tTA/TOP-ICN1 tumor derived cell lines comparing untreated (ICN1-On) cells to 24-hour doxcycline treated (ICN1-Off) samples |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
NOTCH activation has been recently implicated in human basal-like breast cancers associated with a poor prognosis. To address the role of Notch1 in mammary transformation and mammary tumor initiating cell activity, we developed a doxycycline-regulated model of Notch1-mediated mammary transformation. These mice develop mammary adenocarcinomas that express cytokeratin (CK) 8/18 and contain rare cells that also express keratin 14. In vivo limiting dilution analyses reveal that these mammary tumors exhibit functional heterogeneity and harbor a rare (1/2978) mammary tumor initiating cell population. Using this dox-regulated Notch1 mammary tumor model, we demonstrate that Notch1 inhibition results in mammary tumor regression in vivo and prevents disease recurrence in 4 of 6 tumors tested. Consistent with the in vivo data, Notch1 inhibition reduces mammary tumorsphere forming activity in vitro. Using doxycycline-responsive tumor derived cell lines, we also identify the embryonic stem cell transcription factor Nanog as a novel Notch1-regulated gene in mammospheres. These data indicate that Notch1 contributes to mammary tumor initiating activity and raises the possibility that NOTCH therapeutics may have efficacy in human basal-like breast cancers associated with NOTCH activation.
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| Overall design |
Primary mammary tumors were isolated from two different MMTV-tTA/TOP-ICN1 transgenic mice, minced, enzymatically digested and converted to culture. To identify changes in gene expression in response to ICN1 suppression, tumor-derived cell lines 8534 and 8542 were left untreated (8534-Untreated; 8542-Untreated) or treated with 2ug/ml doxycycline for 24 hours (8534-Dox; 8542-Dox). Cells were collected by scraping and total RNA was isolated, followed by real-time PCR validation of NOTCH1 target gene modulation. RNA samples were further hybridized to Affymetrix mouse genome 430A2.0 arrays.
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| Contributor(s) |
Simmons MJ, Kelliher MA |
| Citation missing |
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| |
| Submission date |
Dec 05, 2011 |
| Last update date |
Feb 11, 2019 |
| Contact name |
Matthew J Simmons |
| Organization name |
UMASS Medical School
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| Department |
Cancer Biology
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| Street address |
364 Plantation St
|
| City |
Worcester |
| State/province |
MA |
| ZIP/Postal code |
01605 |
| Country |
USA |
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| Platforms (1) |
| GPL1261 |
[Mouse430_2] Affymetrix Mouse Genome 430 2.0 Array |
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| Samples (4)
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| Relations |
| BioProject |
PRJNA150081 |
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