Filters
Technology
Platform
GSE39857
Homo sapiens
15 Downloadable Samples
Affymetrix Human Genome U133A Array (hgu133a)
Description
By silencing of RALA, a downstream member of the RAS signal transduction pathway, we aimed to determine whether genes downstream of a mutated KRAS (codon 12 or 13) or a mutated BRAF can have significant functions in colorectal cancer carcinogenesis.
Publication Title
Effects of RAL signal transduction in KRAS- and BRAF-mutated cells and prognostic potential of the RAL signature in colorectal cancer.
Sample Metadata Fields
Specimen part, Cell line, Treatment
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
- 6 Downloadable Samples
- Affymetrix Human Genome U133A Array (hgu133a)
Description
Invasive lobular breast cancer (ILC) is an understudied malignancy with distinct clinical, pathological, and molecular features that distinguish it from the more common invasive ductal carcinoma (IDC). Mounting evidence suggests that estrogen receptor-alpha positive (ER+) ILC has a poor response to Tamoxifen (TAM), but the mechanistic drivers of this are undefined. In the current work, we comprehensively characterize the SUM44/LCCTam ILC model system through integrated analysis of gene expression, copy number, and mutation, with the goal of identifying actionable alterations relevant to clinical ILC that can be co-targeted along with ER to improve treatment outcomes. We show that TAM has several distinct effects on the transcriptome of LCCTam cells, that this resistant cell model has acquired copy number alterations and mutations that impinge on MAPK and metabotropic glutamate receptor (GRM/mGluR) signaling networks, and that pharmacological inhibition of either improves or restores the growth-inhibitory actions of endocrine therapy.
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- Mus musculus
- 24 Downloadable Samples
Illumina HiSeq 2500
Description
Canonical Wnt signaling output is mediated by ß-catenin, which interacts with LEF/TCF transcription factors and recruits a general transcriptional activation complex to its C-terminus. Its N-terminus binds BCL9/9L proteins, which bind co-activators that in mammals contribute to fine-tuning the transcriptional output. We found that a BCL9/9L-dependent gene expression signature was strongly associated with patient outcome in colorectal cancer and that stem cell and mesenchymal genes determine its prognostic value. Abrogating BCL9/9L-ß-catenin signaling in independent mouse colorectal cancer models resulted in virtual loss of these traits, and oncogenic intestinal organoids lacking BCL9/9L proteins proved no longer tumorigenic. Our findings suggest that the BCL9/9L arm of Wnt-ß-catenin signaling sustains a stemness-to-differentiation equilibrium in colorectal cancer, which critically affects disease outcome. Mutational activation of the Wnt pathway is a key oncogenic event in colorectal cancer. Targeting the pathway downstream of activating mutations is challenging, and the therapeutic window is limited by intestinal toxicity. Contrasting with phenotypes caused by inactivating key Wnt pathway components, ablation of BCL9/9L proteins in adult mice indicated that they were dispensable for intestinal homeostasis, consistent with their role in tuning transcription. Cancer stem cells are increasingly recognized as responsible for tumor recurrence. The correlation between stemness traits in colorectal cancer models and BCL9/9L-ß-catenin signaling suggests that high Wnt signaling output is required for their maintenance. Our findings suggest that pruning Wnt-ß-catenin signaling might be well tolerated and prove sufficient for trimming stemness traits and improving disease outcome. Overall design: Examination of Bcl9/9l-knockout versus wild-type transcriptome in murine AOM-DSS tumors, APC-Kras tumors and healthy colocyte extracts.
Publication Title
BCL9/9L-β-catenin Signaling is Associated With Poor Outcome in Colorectal Cancer.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 4 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
Why breast cancers become resistant to tamoxifen despite continued expression of the estrogen receptor alpha (ER) and what factors are responsible for high HER2 expression in these tumors remains an enigma. HOXB7 ChIP analysis followed by validation showed that HOXB7 physically interacts with ER, and that the HOXB7-ER complex enhances transcription of many ER target genes including HER2. Investigating strategies for controlling HOXB7, our studies revealed that MYC, stabilized via phosphorylation mediated by EGFR-HER2 signaling, inhibits transcription of miRNA-196a, a HOXB7 repressor. This leads to increased expression of HOXB7, ER-target genes and HER2. Repressing MYC using small molecule inhibitors reverses these events, and causes regression of breast cancer xenografts. The MYC-HOXB7-HER2 signaling pathway is eminently targetable in endocrine-resistant breast cancer.
Publication Title
HOXB7 Is an ERα Cofactor in the Activation of HER2 and Multiple ER Target Genes Leading to Endocrine Resistance.
Sample Metadata Fields
Cell line, Treatment
View Samples- Mus musculus
- 4 Downloadable Samples
- Affymetrix Mouse Gene 2.1 ST Array (mogene21st)
Description
To investigate the detailed molecular mechanisms for the regulatory role of Dmt1 in colon tumorigenesis, microarray gene expression analysis was performed on normal and tumor colon tissue RNA isolated from 3-month-old CDX2; Dmt1+/+/ApcF/+and CDX2; Dmt1F/F/ApcF/+ mice.
Publication Title
Iron Uptake via DMT1 Integrates Cell Cycle with JAK-STAT3 Signaling to Promote Colorectal Tumorigenesis.
Sample Metadata Fields
Age
View Samples- Mus musculus
- 9 Downloadable Samples
- Illumina HiSeq 2000
Description
KRAS mutations are the ost abundand driver mutations found in lung adenocarcinoma patients. Unfortunately, there are no clinical approved inhibitors available, to directly target mutant forms of KRAS. The aim of the study was to unravel the impact of upstream Egfr activation in signaling of mutated K-ras. We found that upregulation of G12D mutant Kras induced genes was significantly impaired when Egfr was knocked out. Our data suggests that signaling of mutant Kras depends on upstream activation. This finding may be exploited therapeutically by targeting EGFR in KRAS mutant patients. Overall design: We isolated mouse alveolar type II cells and induced the Kras G12D mutation, with and without concomitant Egfr knockout, in vitro. Cells lysates were analyzed 5 days following transgene induction.
Publication Title
JAK-STAT inhibition impairs K-RAS-driven lung adenocarcinoma progression.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Homo sapiens
- 8 Downloadable Samples
- NextSeq 500
Description
Approximately 30% of women diagnosed with ERa breast cancer relapse with metastatic disease following adjuvant treatment with endocrine therapies. The connection between acquisition of drug resistance and invasive potential is poorly understood. In this study, we demonstrate that the type II keratin topological associating domain (TAD) undergoes epigenetic reprogramming in cells that develop resistance to aromatase inhibitors (AI), leading to keratin 80 (KRT80) upregulation. In agreement, an increased number of KRT80-positive cells are observed at relapse in vivo while KRT80 expression associates with poor outcome using several clinical endpoints. KRT80 expression is driven by de novo enhancer activation by sterol regulatory element-binding protein 1 (SREBP1). KRT80 upregulation directly promotes cytoskeletal rearrangements at the leading edge, increased focal adhesion maturation and cellular stiffening, which collectively promote cancer cell invasion. Shear-wave elasticity imaging of tumors from prospectively recruited patients shows that KRT80 levels correlate with stiffer tumors in vivo. Collectively, our data uncover an unpredicted and potentially targetable direct link between epigenetic and cytoskeletal reprogramming promoting cell invasion in response to chronic AI treatment. Overall design: Total RNA profiling of MCF7 breast adenocarcinoma cell line and MCF7 overexpressing KRT80. Experiments were carried out in four replicates in both cell lines.
Publication Title
SREBP1 drives Keratin-80-dependent cytoskeletal changes and invasive behavior in endocrine-resistant ERα breast cancer.
Sample Metadata Fields
No sample metadata fields
View Samples