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| Status |
Public on Aug 19, 2019 |
| Title |
Genome-wide copy number profiling of MCF-7 and fulvestrant-resistant MCF-7/FR cells by SNP microarray. |
| Organism |
Homo sapiens |
| Experiment type |
SNP genotyping by SNP array
Genome variation profiling by SNP array
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| Summary |
Estrogens have been shown to elicit anti-cancer effects against estrogen receptor alpha (ER)-positive breast cancer. We sought to determine the underlying mechanism of therapeutic response. Response to 17b-estradiol was assessed in ER+ breast cancer models with resistance to estrogen deprivation: WHIM16 patient-derived xenografts, C7-2-HI and C4-HI murine mammary adenocarcinomas, and long-term estrogen-deprived MCF-7 cells. As another means to reactivate ER, the anti-estrogen fulvestrant was withdrawn from fulvestrant-resistant MCF-7 cells. Transcriptional, growth, apoptosis, and molecular alterations in response to ER reactivation were measured. 17b-estradiol treatment and fulvestrant withdrawal induced transcriptional activation of ER, and cells adapted to estrogen deprivation or fulvestrant were hypersensitive to 17b-estradiol. ER transcriptional response was followed by an unfolded protein response and apoptosis. Such apoptosis was dependent upon the unfolded protein response, p53, and JNK signaling. Anti-cancer effects were most evident in models exhibiting genomic amplification of the gene encoding ER (ESR1), suggesting that engagement of ER at high levels is cytotoxic. These data indicate that long-term adaptation to estrogen deprivation or ER inhibition alters sensitivity to ER reactivation. In such adapted cells, 17b-estradiol treatment and anti-estrogen withdrawal hyperactivate ER, which drives an unfolded protein response activation and subsequent growth inhibition and apoptosis. 17b-estradiol treatment should be considered as an alternative therapy for anti-estrogen-resistant disease, particularly in patients with tumors harboring ESR1 amplification or overexpression. Furthermore, therapeutic strategies that enhance an unfolded protein response may enhance the therapeutic effects of ER reactivation.
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| Overall design |
Genomic DNA from MCF-7 cells and fulvestrant-resistant MCF-7/FR cells was analyzed by Affymetrix SNP 6 microarray to determine copy number variations.
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| Contributor(s) |
Miller TW, Hosford SR |
| Citation(s) |
31180176 |
| Submission date |
Oct 22, 2018 |
| Last update date |
Aug 19, 2019 |
| Contact name |
Todd Miller |
| E-mail(s) |
todd.w.miller@dartmouth.edu
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| Organization name |
Geisel School of Medicine at Dartmouth
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| Street address |
DHMC One Medical Center Dr, HB-7936
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| City |
Lebanon |
| State/province |
NH |
| ZIP/Postal code |
03756 |
| Country |
USA |
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| Platforms (1) |
| GPL6801 |
[GenomeWideSNP_6] Affymetrix Genome-Wide Human SNP 6.0 Array |
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| Samples (2) |
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| Relations |
| BioProject |
PRJNA497897 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE121631_RAW.tar |
165.6 Mb |
(http)(custom) |
TAR (of CEL, CNCHP, TXT) |
| Processed data included within Sample table |
| Processed data provided as supplementary file |
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