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Gene expression profiling of mouse tumors arising from Keratin 6-positive mammary cells

ABSTRACT: Conventional transgenic and knockout models do not allow selective introduction of oncogenic alterations into the progenitor population of mammary cells; thus, the role of progenitor cells in mammary tumorigenesis is yet unknown. By generating transgenic mice expressing tva – encoding the receptor for avian leukosis virus subgroup A (ALV/A) – from the Keratin 6a (K6) gene promoter, we found that K6+ mammary cells are bipotential progenitor cells, but not stem cells. These K6+ cells were readily induced to form tumors by intraductal injection of RCAS (an ALV/A-derived vector) carrying the gene encoding polyoma middle T antigen. Compared with tumors induced by the same oncogene-expressing virus in transgenic mice expressing tva from the commonly used MMTV LTR or other murine models of breast cancer, tumors in this K6-tva line were unique in that they resemble the normal breast-like subtype of human breast cancer. Consequently, these observations suggest that the cell of origin affects mammary tumor phenotypes. This K6-tva model may be useful for preclinical testing of targeted therapy for normal-like breast cancers in patients. Keywords: Three group comparison

ORGANISM(S): Mus musculus

PROVIDER: GSE20614 | GEO | 2011/05/09

SECONDARY ACCESSION(S): PRJNA124795

REPOSITORIES: GEO

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Gene expression profiling of mouse tumors arising from Keratin 6-positive mammary cells

Project description:Conventional transgenic and knockout models do not allow selective introduction of oncogenic alterations into the progenitor population of mammary cells; thus, the role of progenitor cells in mammary tumorigenesis is yet unknown. By generating transgenic mice expressing tva – encoding the receptor for avian leukosis virus subgroup A (ALV/A) – from the Keratin 6a (K6) gene promoter, we found that K6+ mammary cells are bipotential progenitor cells, but not stem cells. These K6+ cells were readily induced to form tumors by intraductal injection of RCAS (an ALV/A-derived vector) carrying the gene encoding polyoma middle T antigen. Compared with tumors induced by the same oncogene-expressing virus in transgenic mice expressing tva from the commonly used MMTV LTR or other murine models of breast cancer, tumors in this K6-tva line were unique in that they resemble the normal breast-like subtype of human breast cancer. Consequently, these observations suggest that the cell of origin affects mammary tumor phenotypes. This K6-tva model may be useful for preclinical testing of targeted therapy for normal-like breast cancers in patients. Keywords: Three group comparison We carried out Affymetrix array analysis of five RCAS-PyMT-induced tumors each from K6-tva mice and MMTV-tva mice, as well as five mammary tumors from MMTV-PyMT transgenic mice.

2011-05-09 | E-GEOD-20614 | biostudies-arrayexpress

Gene expression profiling of FGFR1 KO mice

Project description:A novel RCAS-Cre-IRES-PyMT (RCI-PyMT) virus was designed to specifically knockout genes of interest in tumors generated in appropriate mutant mouse hosts. We used this tumor knockout, or TuKO, strategy to concisely ablate fgfr1 in PyMT induced mammary tumors in K19-tva/fgfr1loxP/loxP mice. The similarly injected control K19-tva mice developed mammary tumors exhibiting high metastasis penetration to lung, making this an ideal model for breast cancer metastasis. The fgfr1 TuKO tumors showed significantly decreased primary tumor growth, and most importantly, greatly reduced metastasis to lung. Our study suggests that FGFR1 signaling is a key pathway driving breast cancer lung metastasis and that targeting FGFR1 in breast cancer is an exciting approach to inhibit metastasis.

2017-06-12 | GSE85754 | GEO

ZNF217 is an oncogene that promotes a basal phenotype and expansion of a progenitor cell population during breast cancer progression

2015-05-18 | GSE38047 | GEO

ZNF217 is an oncogene that promotes a basal phenotype and expansion of a progenitor cell population during breast cancer progression

Project description:Amplification of 20q13 occurs in 20-30% of primary human breast cancers and correlates with poor prognosis. The transcription factor ZNF217 is a candidate oncogene in 20q13. Patients with breast tumors expressing high ZNF217 had reduced survival and increased resistance to chemotherapy. Inducible Znf217 expression in the mammary epithelium of our transgenic mouse resulted in premalignant and invasive lesions. Znf217 overexpression in a mouse luminal breast cancer model generated primary tumors with heterogeneous epithelial and progenitor cell marker expression and promoted metastasis. The AKT inhibitor triciribine inhibited growth and restored sensitivity to a cytotoxic drug in cells expressing high ZNF217. Triciribine reduced tumor burden in vivo, suggesting that ZNF217 may be a novel drug target. Total RNA was isolated from samples overexpressing ZNF217 (4 NMuMG). RNA was also harvested from each cell line expressing a vector control to use as a reference for each microarray sample analyzed. Total RNA was hybridized to mouse MEEBO arrays as described (http://www.microarray.org/sfgf/meebo.do). Samples were verified to have strong overexpression of ZNF217 by qRT-PCR or Western analysis.

2015-05-18 | E-GEOD-38047 | biostudies-arrayexpress

Astrocytes and microglia establish physical interactions during CNS inflammation

Project description:To investigate astrocyte-microglia interactions in vivo, we took advantage of the recombinant rabies virus (RV). We used glycoprotein G-deficient RV expressing the fluorescent protein mCherry and pseudotyped with glycoprotein EnvA, in combination with GFAP-Cre RABVgp4/TVA transgenic mice that express TVA protein and glycoprotein G in astrocytes under the control of the Gfap promoter. Following injection into GfapRABVgp4/TVA mice, RV initially infects TVA expressing astrocytes, and following its replication RV infect cells in direct contact with astrocytes. We then sorted mCherry+ or mCherry- microglia on EAE mice and prove that microglia that had interacted with astrocytes had a more proinflammatory transcriptional profile.

2022-02-25 | GSE149107 | GEO

Consequences of sEH deletion in the polyoma middle T (PyMT) breast cancer tumor proteome

Project description:The aim of this investigation was to study the consequences of interfering with soluble epoxide hydrolase (sEH) expression on tumor growth and metastasis in genetically modified animals that spontaneously generate tumors without the exogenous application of high concentrations of epoxide mediators or inhibitors. Therefore, breast cancer development was studied in mice expressing the polyoma middle T oncogene (PyMT) under the control of the mouse mammary tumor virus promoter, to induce spontaneous mammary tumors. To facilitate the study of endogenous sEH activity in tumor growth, PyMT mice were then crossed with sEH-/- mice to generate sEH-deficient mice that spontaneously generate breast tumors (so called PyMTsEH mice). For these analyses, primary tumors were removed from 20 week old mice.

2021-09-14 | PXD026214 | Pride

Gene expression profiles from mammary tissue of control mice, small K5M-NM-^TNM-NM-2cat hyperplasia, large K5M-NM-^TNM-NM-2cat hyperplasia and K5M-NM-^TNM-NM-2cat tumor

Project description:Basal-like breast cancer is a heterogeneous disease characterised by the expression of basal cell markers, no oestrogen or progesterone receptor expression and a lack of HER2 overexpression. Recent studies have linked activation of the Wnt/beta-catenin pathway to basal-like breast cancer. Transgenic mice expressing N-terminally truncated stabilised beta-catenin in the mammary basal/myoepithelial cell layer (K5deltaNbetacat strain) develop mammary hyperplasias that progress to invasive carcinomas. Histological and microarray analyses of these lesions have revealed their high similarity to a subset of basal-like human breast tumours with squamous differentiation. As in human basal-like carcinomas, the Myc pathway was found to be activated in the mammary lesions of K5deltaNbetacat mice. Mammosphere and transplantation assays showed that a basal cell population with stem/progenitor characteristics was amplified in K5deltaNbetacat mouse preneoplastic glands. Myc deletion from the mammary basal layer of K5deltaNbetacat mice abolished both basal cell regenerative capacity and tumorigenesis. These results show that Myc is essential for beta-catenin-induced stem cell amplification and tumorigenesis and that basal stem/progenitor cells may be at the origin of a subset of basal-like breast tumours. mammary tissue from K5M-NM-^TNM-NM-2cat mice were dissected at successive stages of development (small hyperplasia (n=5), large hyperplasia (n=5), tumor (n=11) and control (n=4)) for RNA extraction and hybridization on Affymetrix microarrays

2013-12-31 | E-GEOD-43825 | biostudies-arrayexpress

Regulation of mammary luminal cell differentiation and tumorigenesis by p38α

Project description:Mammary stem and progenitor cells are essential for mammary gland homeostasis and are also candidates for cells of origin of mammary tumors. Here, we provide evidence that the protein kinase p38a is required for the differentiation of luminal progenitor cells through modulation of the transcription factors Runx1 and Foxa1. Moreover, using a mouse model for breast cancer initiated by luminal cells, we show that p38a downregulation in mammary epithelial cells reduces tumorigenesis, which correlates with reduced numbers of tumor-initiating cells. Our results identify p38a as a key regulator of luminal progenitor cell fate that facilitates mammary tumor formation.

2017-12-28 | GSE92877 | GEO

Mammary Tissue: Wild type mammary glands vs IGF-IR induced mammary tumors vs IGF-IR independent tumors

Project description:Molecular profiling was used to classify mammary tumors that develop in MTB-IGFIR transgenic mice. It was determined that the primary mammary tumors (PMT), which develop due to elevated expression of the type I insulin-like growth factor receptor (IGF-IR) in mammary epithelial cells, most closely resemble murine tumors with basal-like or mixed gene expression profiles and with human basal-like breast cancers. Downregulation of IGF-IR transgene in MTB-IGFIR tumor-bearing mice leads to the regression of most of the tumors followed by tumor re-appearance in some of the mice. These tumors that re-appear following IGF-IR transgene downregulation do not express the IGF-IR transgene and cluster with murine mammary tumors that express a mesenchymal gene expression profile and with human claudin-low breast cancers. Therefore, IGF-IR overexpression in murine mammary epithelial cells induces mammary tumors with primarily basal-like characteristics while tumors that develop following IGF-IR downregulation express a gene signature that most closely resembles human claudin-low breast tumors.

2011-10-01 | GSE32152 | GEO

Gene expression profiles from mammary tissue of control mice, small K5ΔNβcat hyperplasia, large K5ΔNβcat hyperplasia and K5ΔNβcat tumor

2013-12-31 | GSE43825 | GEO

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