Mus musculus
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ABSTRACT:
PROVIDER: PRJNA290272 | ENA |
REPOSITORIES: ENA
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Project description:WAP-Cre:Ptenf/f:p53lox.stop.lox_R270H composite mice were generated by genetic crossing. In these mice, Pten is deleted and a R270H p53 mutation in the DNA binding domain is induced upon expression of Cre recombinase in pregnancy-identified alveolar progenitors. Tumors were characterized by histology, marker analysis, various bioinformatics methods, high-throughput (HTP) FDA-drug screen as well as orthotopic injection to quantify tumor initiating cells (TICs) and tail-vein injection to identify lung-metastasis. Expression data comparing 2 types of Pten-deficient tumors (spindle and poorly differentiated) with other modles of mouse mammary tumors 2 types of Pten deletion plus p53-R270H mutation tumors (spindle and poorly differentiated) was compared with MMTV-Neu, Spindle Pten-p53-deficient tumors, and wild-type mammary gland cells.
2015-12-15 | E-GEOD-75989 | biostudies-arrayexpress
Project description:The tyrosine kinase ErbB2 positive breast tumors have more aggressive tumor growth, poorer clinical outcome, and more resistance to radiotherapy, chemotherapy and hormone therapy. A humanized anti-ErbB2 monoclonal antibody Herceptin and a small molecules inhibitor Lapatinib were developed and approved by FDA to treat patients with ErbB2 amplification and overexpression. Unfortunately, most ErbB2+ breast cancers do not respond to Herceptin and Lapatinib, and the majority of responders become resistant within 12 months of initial therapy (defined as secondary drug resistance). Such differences in response to Lapatinib treatment is contributed by substantial heterogeneity within ErbB2+ breast cancers. To address this possibility, we carried out transcriptomic analysis of mammary tumors from genetically diverse MMTV-ErbB2 mice. This will help us to have a better understanding of the heterogeneous response to ErbB2 targeted therapy and permit us to design better and more individualized (personalized) treatment strategies for human ErbB2 positive breast cancer. 214 MMTV-ErbB2 mammary tumors and 8 normal mammary glands were analyzed by Affymetrix microarrays.
2014-02-01 | E-GEOD-54582 | biostudies-arrayexpress
Project description:p53 is a crucial tumor suppressor in vertebrates that is frequently mutated in human cancers. Most mutations are missense mutations that render p53 inactive in suppressing tumor initiation and progression. Developing small molecule drugs to convert mutant p53 into an active, wild-type-like conformation is a significant focus for personalized cancer therapy. Prior research indicates that reactivating p53 suppresses cancer cell proliferation and tumor growth in animal models. Early clinical evidence with a compound selectively targeting p53 mutants with substitutions of tyrosine 220 suggests potential therapeutic benefits of reactivating p53 in patients. This study identifies and examines the UCI-1001 compound series as a potential corrector for several p53 mutations. The findings indicate that UCI-1001 treatment in p53 mutant cancer cell lines inhibits growth and reinstates wild-type p53 activities, including DNA binding, target gene activation, and induction of cell death. Cellular thermal shift assays, conformation-specific immunofluorescence staining, and differential scanning fluorometry suggest that UCI-1001 interacts with and alters the conformation of mutant p53 in cancer cells. These initial results identify pyrimidine trione derivatives of the UCI-1001 series as candidates for p53 corrector drug development.
2024-08-05 | GSE273169 | GEO
Project description:Expression data comparing Rb/p53 and p53 deficient mammary tumors and normal mammary tissue
| PRJNA262942 | ENA
Project description:Breast cancer is the second leading cause of cancer related death in American women. Patient care is complicated by inherent tumor heterogeneity that can be classified into at least six intrinsic subtypes. While targeted treatments are standard of care for most subtypes, there remains a clinical need for targeted therapies against basal-like tumors that are typically ‘triple negative breast cancers’. As such, the molecular mechanisms underlying basal-like tumors are under intense investigation to identify genetic drivers and possible drug targets of this subtype. Somatic p53 mutations are one of the most common genetic events in basal-like breast tumors. This genetic foundation primes cells to accumulate secondary genetic aberrations, a subset of which is predicted to promote tumorigenesis. To identify additional drivers of basal-like tumors, a comparative study between human and murine tumors was performed utilizing a p53null mammary transplant murine model. The p53null mammary transplant murine model produced a genomically diverse set of tumors, a subset of which we show resemble the human basal-like subtype. Microarray and sequencing technologies were used to interrogate the secondary genetic aberrations of these murine tumors which were then compared to human basal-like tumors to highlight conserved features. Of the ‘omic’ datasets analyzed, DNA copy number variation produced the largest number of conserved candidate driver genes. These candidate gene lists were further filtered using a DNA-RNA Pearson correlation cutoff of 0.5 and a requirement that the gene was deemed essential in at least one human basal-like cell line from a genome-wide RNA-mediated interference screen database. These steps highlighted seven potential driver genes that are at amplified loci in both murine and human basal-like tumors: Atp11a, Col4a2, Cul4a, Lamp1, Met, Pnpla6, and Tubgcp3. Inhibition of Met using Crizotinib caused Met amplified tumors to regress, confirming that this genetic event is a driver in a subset of p53null transplant mammary tumors. This study identifies MET as a driver of basal-like murine tumors, thus identifying a shared potential driver of human basal-like breast cancer. Our results also highlight the importance of comparative genomic studies for discovering drug targets and for providing models to study whether patient populations are likely to respond to selective targeted treatments.
2016-07-08 | GSE71071 | GEO
Project description:To investigate the impact of combined Rb and p53 loss in mammary tumorigenesis, we used transgenic and viral approaches to delete Rb and p53 floxed alleles specifically in the mouse mammary epithelium. Although MMTV-Cre (NLST) targets stem/bi-potent progenitors in the mammary gland, a subset of MMTV-Cre:Rbf/f;p53f/f mice developed non-mammary tumors. Thus, freshly isolated primary mammary epithelial cells from these animals were transplanted into the mammary fat pads of immunodeficient mice and monitored for tumor formation. In addition, primary MECs were isolated from Cre-negative Rbf/f;p53f/f mice, infected with Ad-Cre followed by orthotopic transplantation. In all these cases, resulting tumors shared similar spindle-shape histology, expressed high levels of vimentin, a mesenchymal marker, but not E-cadherin, a luminal marker, and were classified as adeno-sacrcomatoid/spindle-cell/mesenchymal-like breast cancer. We used aCGH to detect copy number alterations associated with Rb/p53 deletion. Tumor DNAs from MMTV-Cre: Rbf/f;p53f/f and Ad-Cre: Rbf/f;p53f/f conditional mutant mice are being compared to pooled tail DNAs in order to identify common alterations associated with Rb/p53 deficient tumorigenesis
2014-10-07 | E-GEOD-62101 | biostudies-arrayexpress
Project description:Gene expression profiles of "spontaneous" and transplanted topotecan-resistant BRCA1;P53-deficient mammary tumors and their matched untreated controls
2010-01-05 | E-NCMF-28 | biostudies-arrayexpress
Project description:We have studied in vivo responses of spontaneous Brca1- and p53-deficient mouse mammary tumors to treatment with doxorubicin, docetaxel or cisplatin.
2007-06-18 | E-NCMF-5 | biostudies-arrayexpress
Project description:Understanding the genetic architecture of cancer pathways that distinguishes subsets of human cancer is critical to developing new therapies that better target tumors based upon their molecular expression profiles. In this study, we identify an integrated gene signature from multiple transgenic models of epithelial cancers intrinsic to the functions of the Simean virus 40 T/t-antigens that is associated with the biologic behavior and prognosis for several human epithelial tumors. This genetic signature, composed primarily of genes regulating cell replication, proliferation, DNA repair and apoptosis, is not a general cancer signature. Rather, it is uniquely activated primarily in tumors with aberrant p53, Rb or BRCA1 expression, but not in tumors initiated through the overexpression of myc, ras, her2/neu, or Polyoma middle T oncogenes. Importantly, human breast, lung and prostate tumors expressing this set of genes represent subsets of tumors with the most aggressive phenotype and with poor prognosis. The T/t-antigen signature is highly predictive of human breast cancer prognosis. Since this class of epithelial tumors is generally intractable to currently existing standard therapies, this genetic signature identifies potential targets for novel therapies directed against these lethal forms of cancer. Since the these genetic targets have been discovered using mammary, prostate, and lung T/t-antigen mouse cancer models, these models are rationale candidates for use in pre-clinical testing of therapies focused on these biologically important targets.
2007-09-01 | GSE8666 | GEO