An integrative transcriptomics approach identifies miR-503 as a candidate master regulator of the estrogen response
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ABSTRACT:
PROVIDER: PRJNA312816 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR3182150_1.fastq.gz | Fastqsanger.gz | |||
| SRR3182150_2.fastq.gz | Fastqsanger.gz | |||
| SRR3182160_1.fastq.gz | Fastqsanger.gz | |||
| SRR3182160_2.fastq.gz | Fastqsanger.gz | |||
| SRR3182170_1.fastq.gz | Fastqsanger.gz |
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Project description:Estrogen receptor α (ERα) is an important biomarker of breast cancer severity and a common therapeutic target. Recent studies have demonstrated that in addition to its role in promoting proliferation, ERα also protects tumors against metastatic transformation. Current therapeutics antagonize ERα and interfere with both beneficial and detrimental signaling pathways stimulated by ERα. The goal of this study is to uncover the dynamics of coding and non-coding RNA (microRNA) expression in response to estrogen stimulation and identify potential therapeutic targets that more specifically inhibit ERα-stimulated growth and survival pathways without interfering with its protective features. To achieve this, we exposed MCF7 cells (an estrogen receptor positive model cell line for breast cancer) to estrogen and prepared a time course of paired mRNA and miRNA sequencing libraries at ten time points throughout the first 24 hours of the response to estrogen. From these data, we identified three primary expression trendsâ??transient, induced, and repressedâ??that were each enriched for genes with distinct cellular functions. Integrative analysis of paired mRNA and microRNA temporal expression profiles identified miR-503 as the strongest candidate master regulator of the estrogen response, in part through suppression of ZNF217â??an oncogene that is frequently amplified in cancer. We confirmed experimentally that miR-503 directly targets ZNF217 and that over-expression of miR-503 suppresses breast cancer cell proliferation. Overall, these data indicate that miR-503 acts as a potent estrogen-induced tumor suppressor microRNA that opposes cellular proliferation and has promise as a therapeutic for breast cancer. More generally, our work provides a systems-level framework for identifying functional interactions that shape the temporal dynamics of gene expression. Quantification of miRNAs in MCF7 cells responding to estrogen following a period of estrogen starvation. Three independent biological replicates (30 samples: 3 replicates x 10 time points) of MCF7 cells were exposed to 10nM Estradiol for 0, 1, 2, 3, 4, 5, 6, 8, 12 , or 24 hours, and total RNA was extracted from the samples. Total RNA was used to generate paired RNA and miRNA sequencing. The miRNA libraries were prepared using the Bioo Scientific NextFLEX v2 library preparation kit.
2016-08-19 | E-GEOD-78168 | biostudies-arrayexpress
Project description:Estrogen receptor α (ERα) is an important biomarker of breast cancer severity and a common therapeutic target. Recent studies have demonstrated that in addition to its role in promoting proliferation, ERα also protects tumors against metastatic transformation. Current therapeutics antagonize ERα and interfere with both beneficial and detrimental signaling pathways stimulated by ERα. The goal of this study is to uncover the dynamics of coding and non-coding RNA (microRNA) expression in response to estrogen stimulation and identify potential therapeutic targets that more specifically inhibit ERα-stimulated growth and survival pathways without interfering with its protective features. To achieve this, we exposed MCF7 cells (an estrogen receptor positive model cell line for breast cancer) to estrogen and prepared a time course of paired mRNA and miRNA sequencing libraries at ten time points throughout the first 24 hours of the response to estrogen. From these data, we identified three primary expression trendsâ??transient, induced, and repressedâ??that were each enriched for genes with distinct cellular functions. Integrative analysis of paired mRNA and microRNA temporal expression profiles identified miR-503 as the strongest candidate master regulator of the estrogen response, in part through suppression of ZNF217â??an oncogene that is frequently amplified in cancer. We confirmed experimentally that miR-503 directly targets ZNF217 and that over-expression of miR-503 suppresses breast cancer cell proliferation. Overall, these data indicate that miR-503 acts as a potent estrogen-induced tumor suppressor microRNA that opposes cellular proliferation and has promise as a therapeutic for breast cancer. More generally, our work provides a systems-level framework for identifying functional interactions that shape the temporal dynamics of gene expression. Quantification of mRNAs in MCF7 cells responding to estrogen following a period of estrogen starvation. Three independent biological replicates (30 samples: 3 replicates x 10 time points) of MCF7 cells were exposed to 10nM Estradiol for 0, 1, 2, 3, 4, 5, 6, 8, 12 , or 24 hours, and total RNA was extracted from the samples. Total RNA was used to generate paired RNA and miRNA sequencing. RNA libraries were prepared using an Illumina TruSeq stranded mRNA library preparation kit.
2016-08-19 | E-GEOD-78167 | biostudies-arrayexpress
Project description:Estrogen receptor α (ERα) is an important biomarker of breast cancer severity and a common therapeutic target. Recent studies have demonstrated that in addition to its role in promoting proliferation, ERα also protects tumors against metastatic transformation. Current therapeutics antagonize ERα and interfere with both beneficial and detrimental signaling pathways stimulated by ERα. The goal of this study is to uncover the dynamics of coding and non-coding RNA (microRNA) expression in response to estrogen stimulation and identify potential therapeutic targets that more specifically inhibit ERα-stimulated growth and survival pathways without interfering with its protective features. To achieve this, we exposed MCF7 cells (an estrogen receptor positive model cell line for breast cancer) to estrogen and prepared a time course of paired mRNA and miRNA sequencing libraries at ten time points throughout the first 24 hours of the response to estrogen. From these data, we identified three primary expression trends—transient, induced, and repressed—that were each enriched for genes with distinct cellular functions. Integrative analysis of paired mRNA and microRNA temporal expression profiles identified miR-503 as the strongest candidate master regulator of the estrogen response, in part through suppression of ZNF217—an oncogene that is frequently amplified in cancer. We confirmed experimentally that miR-503 directly targets ZNF217 and that over-expression of miR-503 suppresses breast cancer cell proliferation. Overall, these data indicate that miR-503 acts as a potent estrogen-induced tumor suppressor microRNA that opposes cellular proliferation and has promise as a therapeutic for breast cancer. More generally, our work provides a systems-level framework for identifying functional interactions that shape the temporal dynamics of gene expression.
2016-08-19 | GSE78168 | GEO
Project description:Estrogen receptor α (ERα) is an important biomarker of breast cancer severity and a common therapeutic target. Recent studies have demonstrated that in addition to its role in promoting proliferation, ERα also protects tumors against metastatic transformation. Current therapeutics antagonize ERα and interfere with both beneficial and detrimental signaling pathways stimulated by ERα. The goal of this study is to uncover the dynamics of coding and non-coding RNA (microRNA) expression in response to estrogen stimulation and identify potential therapeutic targets that more specifically inhibit ERα-stimulated growth and survival pathways without interfering with its protective features. To achieve this, we exposed MCF7 cells (an estrogen receptor positive model cell line for breast cancer) to estrogen and prepared a time course of paired mRNA and miRNA sequencing libraries at ten time points throughout the first 24 hours of the response to estrogen. From these data, we identified three primary expression trends—transient, induced, and repressed—that were each enriched for genes with distinct cellular functions. Integrative analysis of paired mRNA and microRNA temporal expression profiles identified miR-503 as the strongest candidate master regulator of the estrogen response, in part through suppression of ZNF217—an oncogene that is frequently amplified in cancer. We confirmed experimentally that miR-503 directly targets ZNF217 and that over-expression of miR-503 suppresses breast cancer cell proliferation. Overall, these data indicate that miR-503 acts as a potent estrogen-induced tumor suppressor microRNA that opposes cellular proliferation and has promise as a therapeutic for breast cancer. More generally, our work provides a systems-level framework for identifying functional interactions that shape the temporal dynamics of gene expression.
2016-08-19 | GSE78167 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2016-08-19 | E-GEOD-78169 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below.
2016-08-19 | GSE78169 | GEO
Project description:Estrogen receptor α (ERα) is an important biomarker of breast cancer severity and a common therapeutic target. In response to estrogen, ERα stimulates a dynamic transcriptional program including both coding and noncoding RNAs. We generate a fine-scale map of expression dynamics by performing a temporal profiling of both messenger RNAs (mRNAs) and microRNAs (miRNAs) in MCF-7 cells (an ER+ model cell line for breast cancer) in response to estrogen stimulation. We identified three primary expression trends-transient, induced, and repressed-that were each enriched for genes with distinct cellular functions. Integrative analysis of mRNA and miRNA temporal expression profiles identified miR-503 as the strongest candidate master regulator of the estrogen response, in part through suppression of ZNF217-an oncogene that is frequently amplified in cancer. We confirmed experimentally that miR-503 directly targets ZNF217 and that overexpression of miR-503 suppresses MCF-7 cell proliferation. Moreover, the levels of ZNF217 and miR-503 are associated with opposite outcomes in breast cancer patient cohorts, with high expression of ZNF217 associated with poor survival and high expression of miR-503 associated with improved survival. Overall, these data indicate that miR-503 acts as a potent estrogen-induced candidate tumor suppressor miRNA that opposes cellular proliferation and has promise as a novel therapeutic for breast cancer. More generally, our work provides a systems-level framework for identifying functional interactions that shape the temporal dynamics of gene expression.
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Project description:Cutaneous melanoma is the most aggressive skin cancer showing high mortality at advanced clinical stages. Platelet-Derived Growth Factor Receptor alpha (PDGFR-alpha) is known to strongly inhibit melanoma and endothelial cells proliferation, in vitro as well in vivo. PDGFR-alpha expression has been found to be reduced in metastatic human melanoma-biopsies, as compared to benign nevi-biopsies, thus implying a negative selection of PDGFR-alpha expressing cells, in melanoma. In the present study PDGFR-alpha was transiently overexpressed in endothelial (HUVEC) and melanoma (SK-Mel-28) human cells; a strong anti-proliferation effect was observed, along with profound effects on mRNA and miRNA expression. In detail, gene-expression profiling showed that PDGFR-alpha over-expression affects the expression of 82 transcripts in HUVEC (41 up-, 41 down-regulated), and 52 Transcripts in SK-Mel-28 (43 up-, 9 down-regulated). Finally, a miRNA profiling showed that 14 miRs are up-regulated and 39 are down-regulated in PDGFR-alpha overexpressing cells. Accurate validation with alternative techniques demonstrated that CXCL10 is one of the most significantly up-regulated at both gene- and protein level, in combination with a strong down-regulation of miR-503 in both HUVEC and SK-Mel-28 overexpressing PDGFR-alpha. We then demonstrate that CXCL10 is a validated miR-503 target, and that the anti-proliferation effect of PDGFR-alpha is reverted by specific CXCL-10 neutralization. In conclusion, PDGFR-alpha overexpression strongly inhibits endothelial- and melanoma- proliferation in a CXCL-10 dependent way, by significantly down-regulating miR-503 expression. This data set contains the results of the mRNA analysis.
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