 |
 |
GEO help: Mouse over screen elements for information. |
|
| Status |
Public on Feb 05, 2017 |
| Title |
Candidate ERalpha targets for DNA methylation-mediated gene silencing |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
|
| Summary |
DNA methylation of specific CpG sites associates with estrogen receptor α (ERα)-positive status in human breast cancer. Therefore, ERα may regulate gene expression in part via DNA methylation. This hypothesis was tested in a panel of antihormone-resistant T47D and MCF-7 cells with varying levels of ERα expression/activity that were derived by long-term fulvestrant treatment and by estrogen deprivation. Using Agilent’s Whole Human Genome 4x44K v2 gene expression microarrays, the intersection of ERα inversely-related genes and genes induced by the DNA methyltransferase-inhibitor decitabine were identified and revealed 39 candidate ERα DNA methylation targets. Enrichment analysis indicated over-representation of ERα-binding sites, basal-up/luminal-down markers, cancer stem cell genes, epithelial-mesenchymal transition (EMT) genes, inflammatory genes and tumor suppressors.
Kaplan-Meier survival curve and Cox proportional hazard regression analyses indicated these candidate targets predicted poor distant metastasis-free survival among 2,116 breast cancer patients. The basal and EMT genes LCN2 and IFI27 showed the greatest inverse relationship with ERα expression/activity and contain ERα-binding sites, therefore they were selected for validation. LCN2 and IFI27 CpG methylation levels, quantitated by pyrosequencing, were inversely related to ERα expression/activity in wild-type and antihormone-resistant ERα-negative T47D cells, in ERα-negative T47D cells infected with lentiviral ERα, and in a panel of 11 breast cancer cell lines.
Implications: ERα directs DNA methylation-mediated silencing of specific genes, such as basal markers, and thereby may in part program breast cancers as the prognostically more favorable luminal subtype. Thus, genes that can be methylated in an ERα-dependent manner may serve as predictive biomarkers in breast cancer.
|
| |
|
| Overall design |
The intersection of ERα inversely-related genes and decitabine (DAC)-induced genes was determined. This intersection represented the set of genes that fulfilled the following criteria: i) genes induced by DAC versus CON-treated wild-type T47D cells, ii) genes up-regulated in each of the ERα-low/negative cell lines, i.e., T47D/FUL, T47D/ED1, and T47D/ED2 cells, versus wild-type T47D cells, iii) genes down-regulated by 17β-estradiol (E2) in T47D/ED2/E2 versus T47D/ED2 cells, iv) genes up-regulated in ERα-low MCF7/FUL week 8 versus wild-type MCF-7 cells, and v) genes down-regulated in ERα-positive MCF-7/FUL week 21 versus ERα-low MCF-7/FUL week 8 cells. These selection criteria pinpointed 39 high-value candidates for ERα-mediated silencing via DNA methylation.
|
| |
|
| Contributor(s) |
Ariazi EA, Taylor JC, Black MA, Nicolas E, Slifker MJ, Boyd J |
| Citation(s) |
28108626 |
| Submission date |
Aug 12, 2016 |
| Last update date |
Jan 09, 2018 |
| Contact name |
Eric A. Ariazi |
| E-mail(s) |
eric.ariazi@verizon.net
|
| Organization name |
Fox Chase Cancer Center
|
| Street address |
333 Cottman Avenue
|
| City |
Philadelphia |
| State/province |
PA |
| ZIP/Postal code |
19111 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL13497 |
Agilent-026652 Whole Human Genome Microarray 4x44K v2 (Probe Name version) |
|
| Samples (26)
|
| GSM2276609 |
T47D/FUL_fulvestrant-treated_36weeks_rep2 |
| GSM2276610 |
T47D/ED1_estrogen-deprived_52weeks_rep1 |
| GSM2276611 |
T47D/ED1_estrogen-deprived_52weeks_rep2 |
| GSM2276612 |
T47D/ED2_estrogen-deprived_62weeks_rep1 |
| GSM2276613 |
T47D/ED2_estrogen-deprived_62weeks_rep2 |
| GSM2276614 |
T47D/ED2/E2_estrogen-deprived_62weeks_E2-treated_24 weeks_rep1 |
| GSM2276615 |
T47D/ED2/E2_estrogen-deprived_62weeks_E2-treated_24 weeks_rep2 |
| GSM2276616 |
T47D/ED2/E2_estrogen-deprived_62weeks_E2-treated_38 weeks_rep1 |
| GSM2276617 |
T47D/ED2/E2_estrogen-deprived_62weeks_E2-treated_38 weeks_rep2 |
| GSM2276618 |
MCF7_wild-type_rep1 |
| GSM2276619 |
MCF7_wild-type_rep2 |
| GSM2276620 |
MCF7_wild-type_rep3 |
| GSM2276621 |
MCF7/FUL1_fulvestrant-treated_week8_rep1 |
| GSM2276622 |
MCF7/FUL1_fulvestrant-treated_week8_rep2 |
| GSM2276623 |
MCF7/FUL1_fulvestrant-treated_week8_rep3 |
| GSM2276624 |
MCF7/FUL1_fulvestrant-treated_week21_rep1 |
| GSM2276625 |
MCF7/FUL1_fulvestrant-treated_week21_rep2 |
| GSM2276626 |
T47D_control-treated_96h_rep1 |
| GSM2276627 |
T47D_control-treated_96h_rep2 |
| GSM2276628 |
T47D_control-treated_96h_rep3 |
| GSM2276629 |
T47D_decitabine-treated_96h_rep1 |
| GSM2276630 |
T47D_decitabine-treated_96h_rep2 |
| GSM2276631 |
T47D_decitabine-treated_96h_rep3 |
|
| Relations |
| BioProject |
PRJNA338758 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE85536_RAW.tar |
231.8 Mb |
(http)(custom) |
TAR (of TXT) |
| Processed data included within Sample table |
|
|
|
|
 |
Less...
More...