Chemotherapy resistant prostate cancer is a major clinical problem. When the prostate cancer has become androgen deprivation resistant, one of the few treatment regimens left is chemotherapy. There is a strong connection between a cancer's stem cell like characteristics and drug resistance. By performing RNA-seq we observed several factors associated with stem cells being strongly up-regulated by the estrogen receptor ß variants, ß2 and ß5. In addition, most of these factors were also up-regulated by hypoxia. One mechanism of chemotherapy resistance was expression of the hypoxia-regulated, drug transporter genes, where especially ABCG2 and MDR1 were shown to be expressed in recurrent prostate cancer and to cause chemotherapy resistance by efficiently transporting drugs like docetaxel out of the cells. Another mechanism was expression of the hypoxia-regulated notch3 gene, which causes chemotherapy resistance in urothelial carcinoma, although the mechanism is unknown. It is well known that hypoxic signaling is involved in increasing chemotherapy resistance. Regulation of the hypoxic factors, HIF-1a and HIF-2a is very complex and extends far beyond hypoxia itself. We have recently shown that two of the estrogen receptor ß variants, estrogen receptor ß2 and ß5, bind to and stabilize both HIF-1a and HIF-2a proteins leading to expression of HIF target genes. This study suggests that increased expression of the estrogen receptor ß variants, ß2 and ß5, could be involved in development of a cancer's stem cell characteristics and chemotherapy resistance, indicating that targeting these factors could prevent or reverse chemotherapy resistance and cancer stem cell expansion. Overall design: Examination of the transcriptome changed by two estrogen reseptor beta variants (ERbeta2 and ERbeta5). Control (lacking expression) and variant expressing cells in two repeats
The estrogen receptor variants β2 and β5 induce stem cell characteristics and chemotherapy resistance in prostate cancer through activation of hypoxic signaling.
Specimen part, Subject
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Modeling a lethal prostate cancer variant with small-cell carcinoma features.
Specimen part, Disease
View SamplesPurpose: Small-cell prostate carcinoma (SCPC) morphology predicts for a distinct clinical behavior, resistance to androgen ablation, and frequent but short responses to chemotherapy. The model systems we report reflect the biology of the human disease and can be used to improve our understanding of SCPC and to develop new therapeutic strategies for it.
Modeling a lethal prostate cancer variant with small-cell carcinoma features.
Specimen part
View SamplesWe created a comprehensive tRNA deletion library in yeast and characterized the phenotypic and further characterized the molecular changes in a subset of deletion strains
A comprehensive tRNA deletion library unravels the genetic architecture of the tRNA pool.
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View SamplesWe used microarrays to study the global gene expression and identified differentially expressed genes in CHD1 knockdown PC-3 cells and CHD1 KO LNCaP cells, aiming to identify genes and pathways that are regulated by CHD1
Synthetic essentiality of chromatin remodelling factor CHD1 in PTEN-deficient cancer.
Cell line
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Targeting poly(ADP-ribose) polymerase and the c-Myb-regulated DNA damage response pathway in castration-resistant prostate cancer.
Cell line
View SamplesAnalysis of AR-regulation of gene expression. The hypothesis tested in the present study was that AR influences the expression of genes that participate in important bioprocesses in prostate cancer cells, including cell cycle, DNA replication, recombination and repair. Results provide important information on AR-responsive genes that may be crucial to the cell survival and the progression of prostate cancer.
Targeting poly(ADP-ribose) polymerase and the c-Myb-regulated DNA damage response pathway in castration-resistant prostate cancer.
Cell line
View SamplesAnalysis of c-Myb-regulation of gene expression. The hypothesis tested in the present study was that c-Myb influences the expression of specific sets of genes that are involved in cell cycle, DNA replication, recombination and repair. Results provide important information on c-Myb-responsive genes that may be crucial to the cell survival and the progression of prostate cancer.
Targeting poly(ADP-ribose) polymerase and the c-Myb-regulated DNA damage response pathway in castration-resistant prostate cancer.
Cell line
View SamplesWe analyzed the changes in the spinal cord transcriptome after a spinal cord contusion injury and MSC or OEC transplantation. The cells were injected immediately or 7 days after the injury. The mRNA of the spinal cord injured segment was extracted and analyzed by microarray at 2 and 7 days after cell grafting.
Gene expression changes in the injured spinal cord following transplantation of mesenchymal stem cells or olfactory ensheathing cells.
Treatment
View SamplesInterferon is effective at inducing complete remissions in patients with Chronic Myelogenous Leukemia (CML), and evidence supports an immune mechanism. Here we show that the Type I Interferons (alpha and beta) regulate expression of the Interferon consensus sequence binding protein (ICSBP) in bcr-abl transformed cells and as shown previously for ICSBP, induce a vaccine-like immunoprotective effect in a murine model of bcr-abl induced leukemia. We identify the chemokines CCL6 and CCL9 as genes prominently induced by the Type I Interferons and ICSBP, and demonstrate that these immunomodulators are required for the immunoprotective effect of ICSBP expression. Insights into the role of these chemokines in the anti-leukemic response of interferons suggest new strategies for immunotherapy of CML.
ICSBP-mediated immune protection against BCR-ABL-induced leukemia requires the CCL6 and CCL9 chemokines.
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