Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

RB pathway deregulation promotes invasion and disease progression in a mouse model of MYC-overexpressing mammary tumorigenesis

ABSTRACT: Breast cancer is a highly heterogeneous disease that is categorized into distinct tumor subtypes based on specific molecular attributes, which ultimately influence therapeutic options. Unlike ER+ and/or HER2+ cancers that are subject to specific targeted therapies, triple negative breast cancers (TNBCs) do not express these receptors, which leaves patients with limited treatment options. Thus, significant focus has been placed on identifying molecular attributes of basal-like disease that could be used to develop and/or direct novel treatment regimens. Activation of MYC signaling and inactivation of the RB-pathway are frequent events in many types of human cancers. These pathways influence many biological processes, such as cell proliferation, that contribute to the aggressiveness and therapeutic response of tumors. The current study examines the interaction of the MYC and RB pathways in mammary epithelial cell tumorigenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE40545 | GEO | 2013/08/01

SECONDARY ACCESSION(S): PRJNA174251

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

RB pathway deregulation promotes invasion and disease progression in a mouse model of MYC-overexpressing mammary tumorigenesis

Project description:Breast cancer is a highly heterogeneous disease that is categorized into distinct tumor subtypes based on specific molecular attributes, which ultimately influence therapeutic options. Unlike ER+ and/or HER2+ cancers that are subject to specific targeted therapies, triple negative breast cancers (TNBCs) do not express these receptors, which leaves patients with limited treatment options. Thus, significant focus has been placed on identifying molecular attributes of basal-like disease that could be used to develop and/or direct novel treatment regimens. Activation of MYC signaling and inactivation of the RB-pathway are frequent events in many types of human cancers. These pathways influence many biological processes, such as cell proliferation, that contribute to the aggressiveness and therapeutic response of tumors. The current study examines the interaction of the MYC and RB pathways in mammary epithelial cell tumorigenesis. Mouse mammary epithelial cells were isolated and sub-cultured. Adenoviral expression of Cre-recombinase was used to delete the RB and/or p53 genes, and retrovirus was used to achieve MYC overexpression (OE). Proliferating cells were harvested for each condition, and RNA was isolated for analyses.

2013-08-01 | E-GEOD-40545 | biostudies-arrayexpress

Cooperativity of Rb, Brca1, and p53 and malignant breast cancer evolution

Project description:The dire need for more effective treatments for clinically aggressive breast cancers has motivated intensive investigations into their cellular and molecular etiology. Breast cancers that are “triple-negative” for the clinical markers, ESR1, PGR, and HER2, typically belong to the Basal-like molecular subtype. Defective Rb, p53, and Brca1 pathways are each associated with triple-negative and Basal-like subtypes. Our mouse genetic studies demonstrate that concomitant inactivation of all three pathways in mammary epithelium has an additive effect on tumor latency, and predisposes highly penetrant, metastatic, adenocarcinomas. These tumors are poorly differentiated with histologic features that are common among human Brca1-mutated tumors, including heterogeneous morphology, metaplasia, and necrosis. Transcriptomic analyses demonstrated that the tumors shared attributes of both Basal-like and Claudin-low signatures, two molecular subtypes encompassed by the broader triple-negative category defined by clinical markers. Ex vivo tumorsphere formation, which was suppressed by Notch and Wnt pathway inhibition, and tumor antigen profiles and are consistent with enrichment of stem-like and luminal progenitor cells among these tumors. These studies establish a novel mouse model of malignant breast cancer based on events in the human disease and underscore the non-reciprocal requirements of three canonical tumor suppressor pathways in breast cancer evolution. Morphogenetic pathways may provide additional avenues for targeted therapeutic intervention. Gene expression analysis of mouse mammary tumors with perturbation of Rb family pathways, p53, and/or Brca1 are compared to other mouse model tumors (n=152)

2011-12-17 | E-GEOD-34479 | biostudies-arrayexpress

Cooperativity of Rb, Brca1, and p53 and malignant breast cancer evolution (MFT121 p53f/f Brca1f/f)

Project description:Breast cancers that are “triple-negative” for the clinical markers ESR1, PGR, and HER2 typically belong to the Basal-like molecular subtype. Defective Rb, p53, and Brca1 pathways are each associated with triple-negative and Basal-like subtypes. Our mouse genetic studies demonstrate that the combined inactivation of Rb and p53 pathways is sufficient to suppress the physiological cell death of mammary involution. Furthermore, concomitant inactivation of all three pathways in mammary epithelium has an additive effect on tumor latency and predisposes highly penetrant, metastatic adenocarcinomas. The tumors are poorly differentiated and have histologic features that are common among human Brca1-mutated tumors, including heterogeneous morphology, metaplasia, and necrosis. Gene expression analyses demonstrate that the tumors share attributes of both Basal-like and Claudin-low signatures, two molecular subtypes encompassed by the broader, triple-negative class defined by clinical markers. These studies establish a unique animal model of aggressive forms of breast cancer for which there are no effective, targeted treatments. Rb, p53, and Brca1 are associated with inherited forms of cancer, but defects in these pathways are also found together in a subset of breast cancer patients without a family history of the disease. Simultaneous inactivation of all three pathways causes more aggressive disease than do pair-wise combinations, indicating that the pathways play non-overlapping roles in tumor prevention. We investigated the effect of perturbation of Rb family pathways, p53, and/or Brca1 in mouse mammary epithelium. Eighteen tumors were compared to normal spleen DNA.

2012-09-18 | E-GEOD-40925 | biostudies-arrayexpress

Cisplatin-induced gene expression changes in triple-negative breast cancer (TNBC) cells

Project description:Breast cancers lacking receptors for estrogen, progesterone or HER2 on their cell surface are called triple-negative breast cancers (TNBCs). TNBCs account for ~15-20% of all invasive breast cancers and do not benefit from anti-hormonal or anti-HER2 treatments. Although patients with TNBC can initially respond to chemotherapy, they do have worse overall prognosis compared to other breast cancer subtypes. Unfortunately, TNBCs lack clear targetable ‘driver’ oncogenes. Thus, there is an unmet need for strategies to improve the therapeutic options for these patients. We used microarrays to assess differences in gene expression in triple-negative breast cancer cells in response to the platinum-based chemotherapeutic agent cisplatin. The purpose was to find drug induced changes in gene expression level that could differentiate cisplatin sensitive from cisplatin resistant TNBC cell lines.

2017-08-26 | GSE103115 | GEO

Understanding BRCA1 function in INK4-RB deficient tumors

Project description:Most BRCA1-deficient BLBCs carry a dysfunctional INK4-RB pathway. Thus, we have created genetically engineered mice with Brca1 loss and deletion of p16INK4A, or separately p18INK4C, to model the deficient INK4-RB signaling in human BLBC. By using these mutant mice and human BRCA1 deficient and proficient breast cancer tissues and cells, we tested if there exists a druggable target in BRCA1 deficient breast cancers.

2021-01-27 | GSE155239 | GEO

Expression data from control, Rb KO and Rb/Myc DKO tissues (villi and crypts)

Project description:Loss of Myc corrects abrrant transcription in Rb KO villi, while these genetic manipulation does not lead to major gene expression changes in crypts. We used Affymetrix microarrays to profile the global gene expression changes caused by loss of Rb and Rb/Myc.

2015-07-20 | GSE56007 | GEO

Targeting the vulnerability of RB tumor suppressor loss in triple negative breast cancer

Project description:Approximately 30% of TNBCs exhibit loss of function of the RB tumor suppressor. The study used RNA sequencing to profile RB-proficient and RB-deficient TNBC cases that were defined based on immunostaining for RB and p16ink4a. The analyses revealed that RB-deficient TNBC cases express elevated levels of DNA replication and mitotic genes that could serve as the basis for increased sensitivity to drugs targeting cell cycle checkpoints.

2018-01-05 | GSE108757 | GEO

Cooperativity of Rb, Brca1, and p53 and malignant breast cancer evolution

2011-12-17 | GSE34479 | GEO

Cooperativity of Rb, Brca1, and p53 and malignant breast cancer evolution (MFT121 p53f/f Brca1f/f)

2012-09-18 | GSE40925 | GEO

CREBBP is a novel tumour suppressor in solid tumours

Project description:The contribution of the majority of frequently mutated genes to tumourigenesis is not fully defined. Many aggressive human cancers, such as triple negative breast cancers (TNBCs), have a poor prognosis and lack tractable biomarkers and targeted therapeutic options. Here, we systematically characterize loss-of-function mutations to generate a functional map of novel driver genes in a 3-dimensional model of breast cancer heterogeneity that more readily recapitulates the unfavourable tumour microenvironment in vivo. This identified the histone acetyltransferase CREBBP as a potent tumour suppressor gene whose silencing provided a 3D-specific growth advantage only under oxygen and nutrient deplete conditions. CREBBP protein expression was altered in a substantial proportion of TNBCs as well as several other solid tumours, including endometrial, bladder, ovarian and squamous lung cancers. In multiple primary tumours and cell models, loss of CREBBP activity resulted in upregulation of the FOXM1 transcriptional network. Strikingly, treatment with a range of CDK4/6 inhibitors (CDK4/6i), that indirectly target FOXM1 activity, selectively impaired growth in both CREBBP-altered spheroids and cell line xenografts and patient derived models from multiple tumour types. This study is the first to provide rationale for CREBBP as a biomarker for CDK4/6i response in cancer representing a new treatment paradigm for tumours that harbour CREBBP alterations that have limited therapeutic options.

2022-03-23 | PXD012098 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data