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| Status |
Public on Jan 18, 2020 |
| Title |
IL-1-conferred gene expression pattern in ERa+ BCa and AR+ PCa cells is intrinsic to ERa- BCa and AR- PCa cells and promotes cell survival |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Background: Breast (BCa) and prostate (PCa) cancers are hormone receptor (HR)-driven cancers. Estrogen receptor alpha (ERa) is overexpressed in 70% of diagnosed BCa patients and androgen receptor (AR) is overexpressed in 80-90% of diagnosed PCa patients. Thus, BCa and PCa patients are given therapy that reduces hormone levels or directly blocks HR activity; but most patients eventually develop treatment resistance. 15-30% of BCa patients and ≥ 30% of PCa patients that acquire treatment resistance develop tumors enriched in cancer cells with low or no HR accumulation. Furthermore, 15-20% of BCa patients and 10-20% of PCa patients are intrinsically HR-negative (HR-), and thus, have intrinsic resistance to therapy. We have previously reported that interleukin-1 (IL-1) inflammatory cytokine downregulates ERa and AR mRNA in HR-positive (HR+) BCa and PCa cell lines. Additionally, we had identified pro-survival proteins and processes upregulated by IL-1 in HR+ BCa and PCa cells, that are basally high in HR- BCa and PCa cells. Therefore, we hypothesize that IL-1 confers a conserved gene expression pattern in HR+ BCa and PCa cells that mimics conserved basal gene expression patterns in HR- BCa and PCa cells, to promote HR-independent survival and tumorigenicity. Methods: To identify changes in global gene expression we performed RNA sequencing (RNA-seq) for HR+ BCa and PCa cell lines exposed to IL-1 and for untreated HR- BCa and PCa cell lines. We confirmed expression patterns of select genes by RT-qPCR and used siRNA and/or drug inhibition to silence select genes in BCa and PCa cell lines. We also compared our gene expression data with publicly available data sets from hormone receptor-independent sublines. Finally, we performed Ingenuity Pathway Analysis (IPA) to identify signaling pathways encode by our RNA-seq data set. Results: We identified 350 genes in common between BCa and PCa cells that are induced or repressed by IL-1 in HR+ cells that are, respectively, basally high or low in HR- cells. Among these genes, we identified Sequestome-1 (SQSTM1/p62) and SRY (Sex-Determining Region Y)-Box 9 (SOX9) to be essential for survival of HR- BCa and PCa cell lines. Analysis of publicly available data indicates that p62 and SOX9 expression are elevated in hormone receptor-independent BCa and PCa sublines generated in vitro, suggesting that p62 and SOX9 have a role in acquired treatment resistance. We also assessed HR- cell line viability in response verteporfin, an FDA approved therapy for macular degeneration known to target p62, and we found that verteporfin is cytotoxic for HR- cells lines. Conclusions: Taken together, our 350 gene set can be used to identify novel therapeutic targets and/or biomarkers conserved among acquired (e.g. due to inflammation) or intrinsic hormone receptor-independent BCa and PCa.
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| Overall design |
MCF7 breast cancer cell lines was treated with vehicle control, IL-1 alpha or IL-1 beta for 5 days. MDA-MB-231 breast cancer cell lines was treated with vehicle control for 5 days. At Day 5 RNA was ectracted for RNA-sequencing and other analysis was performed such as western blot and RT-qPCR.
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| Contributor(s) |
Nawas AF, Kanchwala M, Thomas-Jardin SE, Dahl H, Daescu K, Bautista M, Anunobi V, Wong A, Meade R, Mistry R, Ghatwai N, Bayerl F, Xing C, Delk N |
| Citation(s) |
31959131 |
| Submission date |
Aug 27, 2019 |
| Last update date |
Feb 03, 2020 |
| Contact name |
Nikki Delk |
| E-mail(s) |
nad140230@utdallas.edu
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| Phone |
9728832581
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| Organization name |
University of Texas at Dallas
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| Department |
Biological Sciences
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| Street address |
800 West Campbell Road
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| City |
Richardson |
| ZIP/Postal code |
75080 |
| Country |
USA |
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| Platforms (1) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
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| Samples (12)
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| Relations |
| BioProject |
PRJNA562528 |
| SRA |
SRP219393 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE136420_GENES.feature_counts.tab.gz |
455.2 Kb |
(ftp)(http) |
TAB |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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