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Targeting PyMT oncogene to diverse mammary cell populations enhances tumor heterogeneity and generates rare breast cancer subtypes

ABSTRACT: We are generating a new mouse model for breast cancer heterogenaity using lentiviral infection to integrate the sporatically transforming EF1α-PyMT10C or Muc-PyMT10C lentivirus into mouse mammary epithelial cell genomes. We then transplant those cells into cleared mammary fat pads of recipient mice, allowing tumors to develop from luminal , myoepithelial, stem and progenitor cell lineages. We developed a wide variety of tumors including rare histologies such as squamous, tubular, spindloid and lipid rich. We used microarray analysis to compare our mouse model with a microarray analysis of 9 established mouse models (Herschkowitz, J.I. et al. Genome Biology, 2007). Heirarchal clustering was used to establish the molecular subtype of tumors developed through the lentiviral-PyMT mouse model. In addition, micrarray analysis was used in conjunction with GeneSifter and GO ontology to identify unique pathways for each of the rare tumor types.

ORGANISM(S): Mus musculus

PROVIDER: GSE40001 | GEO | 2012/08/10

SECONDARY ACCESSION(S): PRJNA172249

REPOSITORIES: GEO

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Targeting PyMT oncogene to diverse mammary cell populations enhances tumor heterogeneity and generates rare breast cancer subtypes

Project description:Generating a new mouse model for breast cancer heterogenaity. We use lentiviral infection to integrate the sporatically transforming EF1α-PyMT10C or Muc-PyMT10C into mouse mammary epithelial cell genomes. We then transplant those cells into cleared mammary fat pads of recipient mice, allowing tumors to develop from luminal , myoepithelial, stem and progenitor cell lineages. We developed a wide variety of tumors including rare histologies such as squamous, tubular, spindloid and lipid rich. We used microarray analysis to compare our mouse model with a microarray analysis of 9 established mouse models (Herschkowitz, J.I. et al. Genome Biology, 2007). Heirarchal clustering was used to establish the molecular subtype of tumors developed through the lentiviral-PyMT mouse model. In addition, micrarray analysis was used in conjunction with GeneSifter and GO ontology to identify unique pathways for each of the rare tumor types 43 total microarrays were generated from lentiviral-PyMT tumors, MMTV-PyMT transgenic tumors, and embryonic samples . Nine samples were two color arrays run at UNC microarray facility, while 34 were one color arrays run at Huntsman Cancer Instutite. The two color arrays were treated as one color arrays, we used the Cy3 intensity data for analysis. These data were merged and normalized (quantile and combat) with previously published arrays from UNC. Data were filtered on an intrinsic gene set developed in 2007 (Herschkowitz, J.I. et al. Genome Biology, 2007) and clustered using euclidian distance metrics This GEO submission consists of the 34 one color arrays run at Huntsman Cancer Instutite. The nine two color arrays run at UNC microarray facility are not included.

2012-08-09 | E-GEOD-40001 | biostudies-arrayexpress

Comparative oncogenomics identifies breast tumors enriched in functional tumor initiating cells

Project description:The claudin-low subtype is a recently identified rare molecular subtype of human breast cancer that expresses low levels of tight and adherens junction genes and shows high expression of epithelial-to-mesenchymal transition (EMT) genes. These tumors are enriched in gene expression signatures derived from human tumor initiating cells (TIC) and human mammary stem cells. Through cross-species analysis, we discovered mouse mammary tumors that have similar gene expression characteristics as human claudin-low tumors and were also enriched for the human TIC signature. Such claudin-low tumors were similarly rare, but came from a number of distinct mouse models including the p53 null transplant model. Here we present a molecular characterization of fifty p53 null mammary tumors as compared to other mouse models and human breast tumor subtypes. Similar to human tumors, the murine p53 null tumors fell into multiple molecular subtypes including two basal-like, a luminal, a claudin-low, and a subtype unique to this model. The claudin-low tumors also showed high gene expression of EMT inducers, low expression of the miR-200 family, and low to absent expression of both claudin 3 and E-cadherin. These murine subtypes also contained distinct genomic DNA copy number changes some of which are similarly altered in their cognate human subtype counterpart. Finally, limiting dilution transplantation revealed that p53 null claudin-low tumors are highly enriched for TICs as compared to the more common adenocarcinomas arising in the same model, thus providing a novel preclinical mouse model to investigate the therapeutic response of TICs. 107 Agilent CGH and expression microarrays

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Comparative oncogenomics identifies breast tumors enriched in functional tumor initiating cells

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Transcriptional profiling of MMTV-tTA/TOP-ICN1 tumor derived cell lines comparing untreated (ICN1-On) cells to 24-hour doxcycline treated (ICN1-Off) samples

Project description:NOTCH activation has been recently implicated in human basal-like breast cancers associated with a poor prognosis. To address the role of Notch1 in mammary transformation and mammary tumor initiating cell activity, we developed a doxycycline-regulated model of Notch1-mediated mammary transformation. These mice develop mammary adenocarcinomas that express cytokeratin (CK) 8/18 and contain rare cells that also express keratin 14. In vivo limiting dilution analyses reveal that these mammary tumors exhibit functional heterogeneity and harbor a rare (1/2978) mammary tumor initiating cell population. Using this dox-regulated Notch1 mammary tumor model, we demonstrate that Notch1 inhibition results in mammary tumor regression in vivo and prevents disease recurrence in 4 of 6 tumors tested. Consistent with the in vivo data, Notch1 inhibition reduces mammary tumorsphere forming activity in vitro. Using doxycycline-responsive tumor derived cell lines, we also identify the embryonic stem cell transcription factor Nanog as a novel Notch1-regulated gene in mammospheres. These data indicate that Notch1 contributes to mammary tumor initiating activity and raises the possibility that NOTCH therapeutics may have efficacy in human basal-like breast cancers associated with NOTCH activation. Primary mammary tumors were isolated from two different MMTV-tTA/TOP-ICN1 transgenic mice, minced, enzymatically digested and converted to culture. To identify changes in gene expression in response to ICN1 suppression, tumor-derived cell lines 8534 and 8542 were left untreated (8534-Untreated; 8542-Untreated) or treated with 2ug/ml doxycycline for 24 hours (8534-Dox; 8542-Dox). Cells were collected by scraping and total RNA was isolated, followed by real-time PCR validation of NOTCH1 target gene modulation. RNA samples were further hybridized to Affymetrix mouse genome 430A2.0 arrays.

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Uncovering tumor-stroma inter-relationships using quantitative MALDI-Mass spectrometry imaging

Project description:To facilitate analysis of protein expression changes in in situ tumors and stroma, we took advantage of a mouse model that permits conditional activation of the Ser-Thr kinase ROCK within mammary tumor cells. In this study, we undertook MALDI-MSI analysis of tissue samples derived from our conditional ROCK mammary tumor model, to quantify in an unbiased manner, the proteomic changes occurring during the progression of mammary cancers in their specific spatial contexts.

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RNA sequence of ISL1-MSCs and Ctrl-MSCs

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Genome wide DNA methylation analysis of C3(1) SV40TAg mouse model of breast cancer

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