Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Gene expression profiling of PC3 cells stably expressing ERbeta1 and ERbeta2

ABSTRACT: The estrogen receptor (ER)M-NM-21 is successively lost during cancer progression, whereas its splice variant, ERM-NM-22, is expressed in advanced prostate cancer. The latter form of cancer often metastasizes to bone, and we wanted to investigate whether the loss of ERM-NM-21 and/or the expression of ERM-NM-22 affect such signaling pathways in prostate cancer. Using PC3 and 22Rv1 prostate cancer cell lines that stably express ERM-NM-21 or ERM-NM-22, we found that the ERM-NM-2 variants differentially regulate genes known to affect tumor behavior. We found that ERM-NM-21 repressed the expression of the bone metastasis regulator Runx2 in PC3 cells. By contrast, RUNX2 expression was up-regulated at the mRNA level by ERM-NM-22 in PC3 cells, whereas Slug was up-regulated by ERM-NM-22 in both PC3 and 22Rv1 cells. In addition, the expression of Twist1, a factor whose expression strongly correlates with high Gleason grade prostate carcinoma, was increased by ERM-NM-22. In agreement with the increased Twist1 expression, we found increased expression of Dickkopf homolog 1; Dickkopf homolog 1 is a factor that has been shown to increase the RANK ligand/osteoprotegerin ratio and enhance osteoclastogenesis, indicating that the expression of ERM-NM-22 can cause osteolytic cancer. Furthermore, we found that only ERM-NM-21 inhibited proliferation, whereas ERM-NM-22 increased proliferation. The expression of the proliferation markers Cyclin E, c-Myc, and p45(Skp2) was differentially affected by ERM-NM-21 and ERM-NM-22 expression. In addition, nuclear M-NM-2-catenin protein and its mRNA levels were reduced by ERM-NM-21 expression. In conclusion, we found that ERM-NM-21 inhibited proliferation and factors known to be involved in bone metastasis, whereas ERM-NM-22 increased proliferation and up-regulated factors involved in bone metastasis. Thus, in prostate cancer cells, ERM-NM-22 has oncogenic abilities that are in strong contrast to the tumor-suppressing effects of ERM-NM-21. The GFP vs. ERbeta1 comparison was carried out with three replicate dye-swaps, six arrays total. The GFP vs. ERbeta2 comparison was carried out with two replicate dye-swaps, four arrays total.

ORGANISM(S): Homo sapiens

SUBMITTER: Philip Jonsson

PROVIDER: E-GEOD-35095 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Estrogen receptors β1 and β2 have opposing roles in regulating proliferation and bone metastasis genes in the prostate cancer cell line PC3.

Dey Prasenjit P Jonsson Philip P Hartman Johan J Williams Cecilia C Ström Anders A Gustafsson Jan-Åke JÅ

Molecular endocrinology (Baltimore, Md.) 20121001 12

The estrogen receptor (ER)β1 is successively lost during cancer progression, whereas its splice variant, ERβ2, is expressed in advanced prostate cancer. The latter form of cancer often metastasizes to bone, and we wanted to investigate whether the loss of ERβ1 and/or the expression of ERβ2 affect such signaling pathways in prostate cancer. Using PC3 and 22Rv1 prostate cancer cell lines that stably express ERβ1 or ERβ2, we found that the ERβ variants differentially regulate genes known to affect ...[more]

PMID: 23028063

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Project description:ERM-NM-117p is a synthetic peptide corresponding to the sequence P295LMIKRSKKNSLALSLT311 of the estrogen receptor alpha (ERM-NM-1) and initially synthesized to mimic its calmodulin binding site. ERM-NM-117p was subsequently found to elicit estrogenic responses in E2-deprived ERM-NM-1-positive breast cancer cells, increasing proliferation and E2-dependent gene transcription. Surprisingly, in E2-supplemented media, ERM-NM-117p induced apoptosis and modified the actin network, influencing thereby cell motility. Here, we report that ERM-NM-117p induces a massive early (3h) transcriptional activity in breast cancer cell lines SKBR3). Remarkably, about 75% of the significantly modified transcripts were also modified by E2, confirming the pro-estrogenic profile of ERM-NM-117p. The different ER spectra of the used cell lines allowed us to extract a specific ERM-NM-117p signature related to ERM-NM-1 and its variant ERM-NM-136. With respect to ERM-NM-1, the peptide activates nuclear (cell cycle, cell proliferation, nucleic acid and protein synthesis) and extranuclear signaling pathways. In contrast, through ERM-NM-136 it exerts inhibitory events on inflammation and cell cycle and inhibition of EGFR signaling. This is the first work reporting ERM-NM-136 specific transcriptional effects. The fact that a number ERM-NM-117p-induced transcripts is different from those activated by E2 revealed that the apoptosis and actin modifying effects of ERM-NM-117p are independent from the ER-related actions of the peptide. Cells after a 4h incubation with medium containing 10% charcoal stripped FBS were incubated with or without E2 (10-6M) or ERa17p in RPMI 1640 supplemented with 10% charcoal stripped FBS, for 3 hours. Total RNA was isolated using Nucleospin II columns (Macheray-Nagel, Dttren, Germany), according to the manufacturerM-bM-^@M-^Ys instructions. RNA was labeled and hybridized according to the Affymetrix protocol (Affymetrix Gene-Chip Expression Analysis Technical Manual), using the HGU133A plus 2 chip, analyzing a total of 54675 transcripts. Signals were detected by an Affymetrix microarray chip reader.

Project description:The interplay between mitogenic and proinflammatory signaling pathways play key roles in determining the phenotypes and clinical outcomes of breast cancers. We have used global nuclear run-on coupled with deep sequencing to characterize the immediate transcriptional responses of MCF-7 breast cancer cells treated with estradiol, TNFM-NM-1, or both. In addition, we have integrated these data with chromatin immunoprecipitation coupled with deep sequencing for estrogen receptor alpha (ERM-NM-1), the pioneer factor FoxA1 and the p65 subunit of the NF-M-NM-:B transcription factor. Our results indicate extensive transcriptional interplay between these two signaling pathways, which is observed for a number of classical mitogenic and proinflammatory protein-coding genes. In addition, GRO-seq has allowed us to capture the transcriptional crosstalk at the genomic locations encoding for long non-coding RNAs, a poorly characterized class of RNAs which have been shown to play important roles in cancer outcomes. The synergistic and antagonistic interplay between estrogen and TNFM-NM-1 signaling at the gene level is also evident in the patterns of ERM-NM-1 and NF-M-NM-:B binding, which relocalize to new binding sites that are not occupied by either treatment alone. Interestingly, the chromatin accessibility of classical ERM-NM-1 binding sites is predetermined prior to estrogen treatment, whereas ERM-NM-1 binding sites gained upon co-treatment with TNFM-NM-1 require NF-M-NM-:B and FoxA1 to promote chromatin accessibility de novo. Our data suggest that TNFM-NM-1 signaling recruits FoxA1 and NF-M-NM-:B to latent ERM-NM-1 enhancer locations and directly impact ERM-NM-1 enhancer accessibility. Binding of ERM-NM-1 to latent enhancers upon co-treatment, results in increased enhancer transcription, target gene expression and altered cellular response. This provides a mechanistic framework for understanding the molecular basis for integration of mitogenic and proinflammatory signaling in breast cancer. Using GRO-seq and ChIP-seq (ER, FoxA1 and p65) to assay the molecular crosstalk of MCF-7 cells treated with E2, TNFM-NM-1 or both E2+TNFM-NM-1.

Dataset Information

Gene expression profiling of PC3 cells stably expressing ERbeta1 and ERbeta2

Publications

Estrogen receptors β1 and β2 have opposing roles in regulating proliferation and bone metastasis genes in the prostate cancer cell line PC3.

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