Effect of AZD1208 on gene expression in recurrent resistant Myc-CaP tumors grown in castrated mice.
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE59106 | GEO | 2014/12/24
SECONDARY ACCESSION(S): PRJNA254427
REPOSITORIES: GEO
Similar Datasets
Project description:AZD1208 is a novel PIM kinase inhibitor that we have shown inhibits tumorigenesis in tissue recombination models, Myc-CaP allograft models, and human prostate cancer xenografts. We sought to determine the intracellular pathways that are responsible for the anti-tumor effect. To this end we used the tissue recombination protocol to implant MYCCaP cells into castrated mice. MYCCaP cells are an androgen-dependent mouse cell line that overexpresses the oncogene MYC. The mice used for implantation were castrated, so any tumors that result from the grafting procedure are androgen-independent. The grafted mice were divided into a control population receiving vehicle, and a test population receiving AZD1208. The tumors were harvested and in vitro cell lines were made. The new cell lines have been perpetuated in androgen-depleted media. RNA was harvested from three cell lines from mice receiving vehicle, three cell lines from mice receiving AZD1208, and from the parental MYCCaP cell line which was raised in media containing androgen. The RNA was hybridized to nine Affymetrix Mouse Gene 2.0 ST Arrays in the Vanderbilt University microarray processing core.
2014-12-24 | E-GEOD-59106 | biostudies-arrayexpress
Project description:Androgen is critical for the growth of the murine prostate. Castration removes the predominant source of androgen in the mouse, leading to prostatic atrophy and death of epithelial cells. However, studies show that epithelial cells which remain in the castrated prostate are enriched for progenitor activity compared to the intact prostate. We performed gene expression profiling of basal and luminal epithelial cells isolated from paired intact and castrated adult male C57BL/6 mouse prostates to gain insights into the mechanisms promoting survival in castration-resistant epithelial cells.
2015-12-03 | GSE75628 | GEO
Project description:Metastatic prostate cancer is commonly localized in bone and treated with androgen ablation, which is initially highly effective, but eventually results in resistant cancer cells. The decreased dependence on androgen is associated with activation of the androgen receptor (AR) via other growth factor receptor pathways. The current study analyzed global gene expression in bone from castrated and sham operated C57BL/6 mice to identify factors that may be responsible for androgen signaling. Androgen suppression by castration increased the expression of 159 genes with insulin-like growth factor binding protein 5 (IGFBP5) being the most consistently increased. IGFBP5 protein was detected by immune histochemistry in osteoblasts, bone marrow stromal cells and endothelial cells. In vitro treatment of marrow stromal cells with charcoal-stripped serum increased IGFBP5 mRNA expression approximately 25-fold and was reversed by androgen supplementation. Endogenous IGFBP5 was incorporated into extracellular matrix. In addition, treatment of extracellular matrices with exogenous IGFBP5 and IGF-1 or IGF-2 enhanced the growth of immortalized human prostate cells. These results suggest that androgen ablative therapy may increase IGFBP5 in the marrow microenvironment, thereby providing support for the development of therapy resistance prostate cancer cells. Keywords: Bone Marrow Environment, Androgen Suppression, IGFBP5, prostate cancer
2007-06-01 | GSE5775 | GEO
Project description:Metastatic prostate cancer is commonly localized in bone and treated with androgen ablation, which is initially highly effective, but eventually results in resistant cancer cells. The decreased dependence on androgen is associated with activation of the androgen receptor (AR) via other growth factor receptor pathways. The current study analyzed global gene expression in bone from castrated and sham operated C57BL/6 mice to identify factors that may be responsible for androgen signaling. Androgen suppression by castration increased the expression of 159 genes with insulin-like growth factor binding protein 5 (IGFBP5) being the most consistently increased. IGFBP5 protein was detected by immune histochemistry in osteoblasts, bone marrow stromal cells and endothelial cells. In vitro treatment of marrow stromal cells with charcoal-stripped serum increased IGFBP5 mRNA expression approximately 25-fold and was reversed by androgen supplementation. Endogenous IGFBP5 was incorporated into extracellular matrix. In addition, treatment of extracellular matrices with exogenous IGFBP5 and IGF-1 or IGF-2 enhanced the growth of immortalized human prostate cells. These results suggest that androgen ablative therapy may increase IGFBP5 in the marrow microenvironment, thereby providing support for the development of therapy resistance prostate cancer cells. Keywords: Bone Marrow Environment, Androgen Suppression, IGFBP5, prostate cancer
2007-06-01 | GSE5776 | GEO
Project description:The purpose of the study was to characterize the properties of human prostate cancer VCaP tumors pre- and post-castration. The main focus was on androgen signaling, androgen metabolism and steroid synthesis. Results provide valuable information about how castration-resistant tumors (CRPC) are able grow in absence of gonadal androgens. One million VCaP cells were inoculated orthotopically into the dorsolateral prostate of nude mice through an abdominal incision. Tumor growth was followed by serum PSA measurements. Intact mice were sacrificed and tumors were collected 3-14 weeks after inoculation (Intact 1, Intact 2). Mice in the remaining three groups (GNX, CRPC 1, CRPC 2) were castrated by removing the testes. Mice were sacrificed and tumors were collected one day after castration (GNX) or 3-14 weeks after castration (CRPC 1, CRPC 2) in castration-resistant stage. 4 tumors were selected from each study group, totally 20 tumors.
2014-04-21 | E-GEOD-56829 | biostudies-arrayexpress
Project description:Differences in adipose tissue deposition and properties between pig male sex categories, i.e., entire male, immunocastrated and surgically castrated pigs are relatively well characterized, whereas the underlying genetic mechanisms are still not fully understood. To gain the knowledge about the genetic regulation of the differences in adipose tissue deposition, RNA-sequencing approach was used. A total of 83 differentially expressed genes were identified between entire male and immunocastrated pigs, 15 between immunocastrated and surgically castrated pigs and 48 between entire male and surgically castrated pigs by RNA-sequencing of the subcutaneous adipose tissue. Comparing entire male with immunocastrated or surgically castrated pigs, upregulated genes related to extracellular matrix dynamics, and downregulated genes involved in the control of lipid and carbohydrate metabolism were determinated. Moreover, differential gene expression in general indicated a high similarity between immunocastrated and surgically castrated pigs in contrast to entire males, except for several heat shock protein genes which were upregulated in entire male and immunocastrated pigs compared with surgically castrated pigs.
2021-03-03 | GSE164391 | GEO
Project description:The study uses RNA sequencing to profile AZD1208 resistant (AZDR) vs AZD1208 sensitive HSB-2 cells. PIM inhibitor treatment decreases leukemia burden in early T-cell precursor acute lymphoblastic leukemias (ETP-ALL) both in vitro and in vivo. However, prolonged treatment of ETP-ALL with PIM kinase inhibitors results in PIM inhibitor resistance. The analysis revealed that the HOXA9, mTOR, MYC, NF-B, and PI3K-AKT pathways were activated in PIM inhibitor resistant ETP-ALL
2021-09-20 | GSE135545 | GEO
Project description:We report that the phytoestrogen genistein acts as a tissue-specific androgen receptor modulator in mouse using a novel androgen reporter mouse line and gene expression profiling. Genistein is a partial androgen agonist/antagonist in prostate, brain, and testis but not in skeletal muscle or lung. Gene expression profiling has been done from prostates of intact and castrated male mice treated with genistein or vehicle. Gene expression profiling was also done from prostates of estradiol-treated intact male mice. Gene expression profiling from prostates of castrated and intact male mice after 5-day genistein- or vehicle-treatment or after 4-day estradiol- or vehicle-treatment.
2011-08-18 | E-GEOD-31341 | biostudies-arrayexpress
Project description:Castration-resistant prostate cancer is a lethal disease. The cell type(s) that survive androgen-deprivation remain poorly described despite global efforts to understand the various mechanisms of therapy resistance. We recently identified in wild type mouse prostates a rare population of luminal progenitor cells that we called LSCmed according to their FACS profile (Lin?/Sca-1+/CD49fmed). Here we investigated the prevalence and castration resistance of LSCmed in various mouse models of prostate tumorigenesis. In intact mice, we show that LSCmed prevalence remains low (5-10% of epithelial cells) when prostatic androgen receptor signaling unaltered (malignant Hi-Myc mice) but significantly increases in models exhibiting reduced prostatic androgen receptor signaling, rising up to 30% in premalignant tumors (Pb-PRL mice) and to >80% in castration-resistant prostate tumors driven by Pten loss (Ptenpc-/- mice). LSCmed tolerance to androgen deprivation was demonstrated by their persistence (Ptenpc-/-) or further enrichment (Pb-PRL) 2-3 weeks after castration as evidenced by FACS analysis. Transcriptomic analysis revealed that LSCmed represent a unique cell entity as their gene-expression profile is different from luminal and basal/stem cells, but shares markers of each. Their intrinsic androgen signaling is markedly decreased, which explains why LSCmed tolerate androgen-deprivation. This also enlightens why Ptenpc-/- tumors are castration-resistant since LSCmed represent the most prevalent cell type in this model. We validated CK4 as a specific marker for LSCmed on sorted cells and prostate tissues by immunostaining, allowing for the detection of LSCmed in various mouse prostate specimens. In castrated Ptenpc-/- prostates, BrdU staining revealed massive proliferation of CK4+ cells, further demonstrating their key role in castration-resistant prostate cancer progression. In all, this study identifies LSCmed as a probable source of prostate cancer relapse after androgen deprivation and as a new therapeutic target for the prevention of castrate-resistant prostate cancer.
2017-08-15 | E-MTAB-4991 | biostudies-arrayexpress
Project description:Triple-negative breast cancer (TNBC) is the breast cancer (BC) subtype with the poorest outcome. The PIM family of kinases has recently emerged as a factor that is both overexpressed in TNBC samples and associated with poor outcomes. Preclinical data suggest that TNBC that exhibits an elevated MYC oncoprotein expression (MYC+TNBC), accounting for 50% of TNBC cases, is sensitive to PIM inhibition. However, ongoing clinical observations indicate that the efficacy of PIM inhibitors as single agents may be limited in solid tumors, suggesting the need for combination therapies. We conducted drug combination screens to identify a combination that targets PIM and the 20S proteasome (the PIMi/20Si combination) as the most synergistic combination. Following the screening, we used a chemical genetic approach to reveal that the mechanisms of drug synergy involve disruption of protein homeostasis and obstruction of an adaptive resistance mechanism associated with proteasome inhibition. Thus, the PIMi/20Si combination could represent a rational combination therapy against MYC+ TNBC that is readily translatable to early-stage clinical investigations.
2021-05-26 | MSV000087521 | MassIVE