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GSE46222
Homo sapiens
39 Downloadable Samples
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Unlike many other cancers, estrogen receptor-alpha (ER+) breast cancers are associated with cumulative risks of recurrence and death that persist for decades. We show that molecular differences between breast cancers that recur at distant sites early ( 3 years) or late ( 5 years) support a robust molecular predictor of recurrence with Tamoxifen therapy and provide novel insights into the signaling features that differ between these recurrent cancers. We applied a support vector machine with recursive feature elimination to gene expression microarray data using a training-internal crossvalidation workflow that minimizes the gene selection bias problem. The resulting predictor was validated in an independent data set. Performance of the predictor suggests that it is possible to identify patients at increased risk of experiencing an early recurrence who require other treatments to prevent early metastasis. We implemented a Metropolis Sampling algorithm as a random walk to identify the protein-protein interactions (PPI) most closely associated with ER in 8 PPI databases. We then walked the gene expression data for the top PPIs to discover a signaling network driving early and late recurrent breast cancers. Consensus features between the training and validation datasets define a complex and highly connected network with major interactions among nodes including AR, CALD1, CALM(1,2,3), CDK1, EGFR, ESR1, ESR2, MAPK1, and SRC. The complexity illustrates the challenges in directing single agent or simple combination therapies to improve overall survival in ER+ breast cancers that will recur but also suggests potentially novel interventions to address this challenge.
Publication Title
No associated publication
Sample Metadata Fields
Specimen part
View Samples- Rattus norvegicus
- 12 Downloadable Samples
- Affymetrix Rat Genome 230 2.0 Array (rat2302)
Description
Thiazolidinediones increase tissue insulin sensitivity and are protective against worsening of nephropathy and hypertension in diabetes. Mechanisms underlying protection at the renal level likely involve a variety of unknown changes in gene expression. We examined kidney gene expression in obese and lean Zucker rats in response to rosiglitazone (Avandia), a peroxisome proliferator activated receptor (gamma-subtype) agonist. Lean and obese Zucker rats were treated with either control chow or chow with added rosiglitazone (3 mg/kgbw) for 12 weeks (n = 3/group). Total kidney mRNA expression was evaluated using the Affymetrix Rat Genome 230 2.0 GeneChip. 903 probe sets were significantly (P < 0.05) altered with at least 1.5-fold changes between groups. In untreated obese rats, 300 probe sets were increased and 244 decreased, relative to lean. Increased genes included the -subunit of the epithelial sodium channel (ENaC), the thiazide-sensitive Na-Cl cotransporter, and aquaporin 3. Decreased genes included angiotensin converting enzyme, type 1 (ACE1). FatiGO analysis showed that the highest number of altered genes between lean and obese belonged to the categories: ion binding, hydrolase activity, and protein binding. RGZ increased expression of uncoupling protein 1 (UCP1), CD36, and fatty acid binding protein 4 (FAbp4) in both lean and obese rats. In obese rats, 33 genes were normalized by RGZ (no longer different from lean) including ACE1, fatty acid synthase (Fasn), and stearoyl-coenzyme A desaturase 2 (Scd2). Ingenuity Pathways System analysis of genes upregulated by RGZ in obese rats revealed two major nodes affected: PPAR-gamma and tumor necrosis factor alpha (TNF-alpha).
Publication Title
Chronic rosiglitazone therapy normalizes expression of ACE1, SCD1 and other genes in the kidney of obese Zucker rats as determined by microarray analysis.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 12 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
Strigolactones are a novel class of plant hormones produced in roots and regulate shoot and root development. We have previously shown that synthetic strigolactone analogues potently inhibit growth of breast cancer cells and breast cancer stem cells. Here we show that strigolactone analogues inhibit the growth and survival of an array of cancer-derived cell lines representing solid and non-solid cancer cells including: prostate, colon, lung, melanoma, osteosarcoma and leukemic cell lines, while normal cells were minimally affected. Furthermore, we tested the response of patient-matched conditionally reprogrammed normal and prostate cancer cells. The tumor cells exhibited significantly higher sensitivity to the two most potent SL analogues with increased apoptosis compared to their normal counterpart cells. Treatment of cancer cells with strigolactone analogues was hallmarked by increased expression and activity of genes involved in stress signaling, cell cycle arrest and apoptosis. All five strigolactone analogues induced G2/M cell cycle arrest, accompanied with a decrease in the expression level of cyclin B1. Apoptosis was marked by increased percentages of cells in the sub-G1 fraction and was confirmed by Annexin V staining. In conditionally reprogramed matched tumor and normal prostate cells, the cleavage of PARP1 confirmed the specific increase in apoptosis of tumor cells. In summary, Strigolactone analogues are promising candidates for anticancer therapy by their ability to specifically induce cell cycle arrest, cellular stress and apoptosis in tumor cells with minimal effects on growth and survival of normal cells.
Publication Title
Strigolactone analogues induce apoptosis through activation of p38 and the stress response pathway in cancer cell lines and in conditionally reprogrammed primary prostate cancer cells.
Sample Metadata Fields
Cell line, Time
View Samples- Saccharomyces cerevisiae
- 12 Downloadable Samples
- Affymetrix Yeast Genome 2.0 Array (yeast2)
Description
In Saccharomyces cerevisiae, specific genes physically relocate from the nucleoplasm to the nuclear periphery concomitant with transcriptional activation, where they associate with the nuclear pore complex (NPC). We took a genomics approach in order to gain insight into the universality and physiological relevance of the interaction between active genes and the NPC. Using synthetic genetic array (SGA) approach, we identified interactions between components of the SAGA histone acetyltransferase complex and the Mlp and Nup60 subunits of the NPC. Cells lacking these SAGA and NPC components display growth defects under optimal growth conditions, in which cells are grown on rich medium containing the preferred sugar glucose as a carbon source and incubated at their optimal temperature. That growth defects were observed under these non-stress conditions suggests that these interactions are indicative of defects in normal cell physiology. These results are consistent with a model where physical interactions between the NPC and SAGA are important for transcription of constitutively expressed genes. To test this hypothesis, we used microarray analysis to assess changes global transcript levels in the absence of Nup60, Ada2, or Nup60 and Ada2. Microarray analysis reveals that the growth defect in these double mutants is correlated with a synthetic reduction in steady-state transcript levels for numerous genes that are strongly expressed in wildtype cells. These results suggest that SAGA and Nup60 cooperate in transcriptional regulation, and are consistent with a model for global regulation of SAGA-dependent transcription at the NPC.
Publication Title
No associated publication
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 12 Downloadable Samples
Affymetrix Human Genome U133A Array (hgu133a)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Integrated molecular analysis of Tamoxifen-resistant invasive lobular breast cancer cells identifies MAPK and GRM/mGluR signaling as therapeutic vulnerabilities.
Sample Metadata Fields
Treatment
View Samples- Homo sapiens
- 9 Downloadable Samples
- Affymetrix Human Genome U133A Array (hgu133a)
Description
The taxanes, namely Paclitaxel and Docetaxel, are important and widely used cancer chemotherapy drugs in the treatment of invasive and metastatic human breast cancer. Although treatment with the taxanes is beneficial to many patients, drug-responsive tumors in patients with metastatic breast cancer often display resistance to these drugs, either initially or over time following the continued administration of chemotherapy drugs. To investigate the patterns of cross-resistance with the taxane drugs and to identify potential mechanisms of resistance, we generated a series of MDA-MB-231 taxane resistant cell lines.
Publication Title
No associated publication
Sample Metadata Fields
Specimen part, Cell line
View Samples- Homo sapiens
- 8 Downloadable Samples
- Affymetrix Human Genome U133A 2.0 Array (hgu133a2)
Description
Gamma tocotrienol induces apoptosis in breast cancer cells however, the molecular mechanisms are not completely understood.
Publication Title
Gamma-tocotrienol induced apoptosis is associated with unfolded protein response in human breast cancer cells.
Sample Metadata Fields
Cell line
View Samples- Mus musculus
- 8 Downloadable Samples
- Affymetrix Murine Genome U74A Version 2 Array (mgu74av2)
Description
C57BL/6 mice were infected with the GS strain of G. duodenalis and total RNA prepared from the duodenum on day 10. Age matched controls were compared using Affy chips to determine changes in gene expression induced by infection.
Publication Title
Transcriptomic analysis of the host response to Giardia duodenalis infection reveals redundant mechanisms for parasite control.
Sample Metadata Fields
Age, Specimen part
View Samples- Homo sapiens
- 6 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Follistatin is a folliculogenesis regulating protein that has been found in relatively high concentration in the female ovarian tissues. Follistatin acts as an antagonist to the function of Activin, which is often found elevated in ovarian carcinogenesis and thus presents a possibility for therapeutic intervention in controlling ovarian cancer. Most of the ovarian cancer occurs in its ovarian surface epithelium (OSE) cells. Although breast cancer susceptibility gene 1 (BRCA1) is a known tumor suppressor for breast cancer but its role in ovarian cancer is beginning to unfold. We have shown that in ovarian carcinoma cells (SKOV3), stable overexpression of BRCA1 stimulates Follistatin secretion and simultaneously downregulates Activin expression. Moreover, knock down of BRCA1 in immortalized OSE (IOSE) cells from human ovarian tissue demonstrates downregulation of Follistatin secretion with simultaneous up regulation of Activin expression. IOSE cells generated from an ovarian cancer patient with BRCA1 mutation failed to secrete Follistatin in the medium. Our results indicate a novel function for BRCA1 in the form of regulation of the expression of Follistatin in the ovarian cells.
Publication Title
BRCA1 regulates follistatin function in ovarian cancer and human ovarian surface epithelial cells.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Homo sapiens
- 6 Downloadable Samples
- Affymetrix Human Genome U133A Array (hgu133a)
Description
One-third of all ER+ breast tumors treated with endocrine therapy fail to respond, and the remainder are likely to relapse in the future. Almost all data on endocrine resistance has been obtained in models of invasive ductal carcinoma (IDC). However, invasive lobular carcinomas (ILC) comprise up to 15% of newly diagnosed invasive breast cancers diagnosed each year and, while the incidence of IDC has remained relatively constant during the last 20 years, the prevalence of ILC continues to increase among postmenopausal women. We report a new model of Tamoxifen (TAM)-resistant invasive lobular breast carcinoma cells that provides novel insights into the molecular mechanisms of endocrine resistance. SUM44 cells express ER and are sensitive to the growth inhibitory effects of antiestrogens. Selection for resistance to 4-hydroxytamoxifen led to the development of the SUM44/LCCTam cell line, which exhibits decreased expression of estrogen receptor alpha (ER) and increased expression of the estrogen-related receptor gamma (ERR). Knockdown of ERR in SUM44/LCCTam cells by siRNA restores TAM sensitivity, and overexpression of ERR blocks the growth-inhibitory effects of TAM in SUM44 and MDA-MB-134 VI lobular breast cancer cells. ERR-driven transcription is also increased in SUM44/LCCTam, and inhibition of activator protein 1 (AP1) can restore or enhance TAM sensitivity. These data support a role for ERR/AP1 signaling in the development of TAM resistance, and suggest that expression of ERR may be a marker of poor Tamoxifen response.
Publication Title
ERRgamma mediates tamoxifen resistance in novel models of invasive lobular breast cancer.
Sample Metadata Fields
No sample metadata fields
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