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| Status |
Public on Mar 09, 2012 |
| Title |
FOXA1 actively represses the molecular phenotype of basal breast cancers. |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
Breast cancer is a heterogeneous disease comprised of at least five major subtypes. Luminal subtype tumors confer a more favorable patient prognosis, which is in part, attributed to the Estrogen Receptor-α (ER) positivity and anti-hormone responsiveness of these tumors. Expression of the forkhead box transcription factor, FOXA1, also correlates with the luminal subtype and patient survival, but is present in a subset of ER-negative tumors. Similarly, FOXA1 is consistently expressed in luminal breast cancer cell lines even in the absence of ER. In contrast, basal breast cancer cell lines do not express FOXA1, and loss of FOXA1 in luminal cells increases migration and invasion, characteristics of the basal subtype. To delineate an ER-independent role for FOXA1 in maintaining the luminal phenotype, and hence a more favorable prognosis, we performed cDNA microarray analyses on luminal FOXA1-positive, ER-positive (MCF7, T47D) and FOXA1-positive, ER-negative (MDA-MB-453, SKBR3) cell lines in the presence or absence of transient FOXA1 silencing. This resulted in three FOXA1 transcriptomes: (1) a luminal-signature (consistent across cell lines), (2) an ER-positive signature (restricted to MCF7 and T47D) and (3) an ER-negative signature (restricted to MDA-MB-453 and SKBR3). Use of Gene Set Enrichment Analyses (GSEA) as a phenotyping tool revealed that FOXA1 silencing resulted in a transcriptome shift from luminal to basal gene expression signatures. FOXA1 binds to both luminal and basal genes within luminal breast cancer cells, suggesting that it not only transactivates luminal genes, but also represses basal-associated genes. From these results we conclude that FOXA1 controls plasticity between basal and luminal cells, playing a dominant role in repressing the basal phenotype, and thus tumor aggressiveness, in luminal breast cancer cells. Although it has been proposed that FOXA1-targeting agents may be useful for treating luminal tumors, these data suggest that this approach may promote transitions toward a more aggressive cancer.
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| Overall design |
FOXA1 siRNA treated breast cell lines compared directly to nonspecific siRNA treated cell lines using Agilent 4X44 microarrays.
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| Contributor(s) |
Bernardo GM, Ginther CL, Bebek G, Slamon DJ, Keri RA |
| Citation(s) |
22391567 |
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| Submission date |
Jul 27, 2011 |
| Last update date |
Feb 22, 2018 |
| Contact name |
Gina Sizemore |
| E-mail(s) |
gmb15@case.edu
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| Phone |
614-685-9185
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| Organization name |
Ohio State University
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| Street address |
460 W. 12th Avenue
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| City |
Columbus |
| State/province |
OH |
| ZIP/Postal code |
43210 |
| Country |
USA |
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| Platforms (1) |
| GPL4133 |
Agilent-014850 Whole Human Genome Microarray 4x44K G4112F (Feature Number version) |
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| Samples (20)
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| GSM768193 |
Expression of MCF7 cells treated with FOXA1 siRNA for 36hrs |
| GSM768194 |
Expression of MCF7 cells treated with FOXA1 siRNA for 72hrs #1 |
| GSM768195 |
Expression of MCF7 cells treated with FOXA1 siRNA for 72hrs #2 |
| GSM768196 |
Expression of MCF7 cells treated with FOXA1 siRNA for 72hrs #3 |
| GSM768197 |
Expression of MCF7 cells treated with FOXA1 siRNA for 72hrs-ds #1 |
| GSM768198 |
Expression of T47D cells treated with FOXA1 siRNA for 36hrs |
| GSM768199 |
Expression of T47D cells treated with FOXA1 siRNA for 72hrs #1 |
| GSM768200 |
Expression of T47D cells treated with FOXA1 siRNA for 72hrs #2 |
| GSM768201 |
Expression of T47D cells treated with FOXA1 siRNA for 72hrs #3 |
| GSM768202 |
Expression of T47D cells treated with FOXA1 siRNA for 72hrs-ds #1 |
| GSM768203 |
Expression of MB453 cells treated with FOXA1 siRNA for 36hrs |
| GSM768204 |
Expression of MB453 cells treated with FOXA1 siRNA for 72hrs #1 |
| GSM768205 |
Expression of MB453 cells treated with FOXA1 siRNA for 72hrs #2 |
| GSM768206 |
Expression of MB453 cells treated with FOXA1 siRNA for 72hrs #3 |
| GSM768207 |
Expression of MB453 cells treated with FOXA1 siRNA for 72hrs-ds #1 |
| GSM768208 |
Expression of SKBR3 cells treated with FOXA1 siRNA for 36hrs |
| GSM768209 |
Expression of SKBR3 cells treated with FOXA1 siRNA for 72hrs #1 |
| GSM768210 |
Expression of SKBR3 cells treated with FOXA1 siRNA for 72hrs #2 |
| GSM768211 |
Expression of SKBR3 cells treated with FOXA1 siRNA for 72hrs #3 |
| GSM768212 |
Expression of SKBR3 cells treated with FOXA1 siRNA for 72hrs-ds #1 |
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| Relations |
| BioProject |
PRJNA146339 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE31003_RAW.tar |
289.9 Mb |
(http)(custom) |
TAR (of TXT) |
| Processed data included within Sample table |
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