Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA103049 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:We report a mouse model that recapitulates expression of the ETV6-NTRK3 (EN) fusion oncoprotein, the product of the t(12;15)(p13;q25) translocation characteristic of human secretory breast carcinoma. Activation of EN expression in mammary tissues by Whey acidic protein (Wap) promoter-driven Cre leads to fully penetrant, multifocal malignant breast cancer with short latency. We provide genetic evidence that committed bipotent or CD61+ luminal alveolar progenitors, are targets of tumorigenesis. Furthermore, EN transforms these otherwise transient progenitors through activation of the AP1 complex. Given increasing relevance of chromosomal translocations in epithelial cancers, such mice serve as a paradigm for the study of their genetic pathogenesis and cellular origins, and generation of novel preclinical models. In this study, we generated microarray expression profiling data from both genetically marked, FACS-sorted tumor epithelial cells and from unfractionated mammary tumors and normal mammary glands. By using gene set enrichment analysis (GSEA) on these data, we have identified the AP1 transcriptional complex as the major downstream effector of the ETV6-NTRK3 signaling. Experiment Overall Design: Take the advantage of the Cre-lox system and a floxed lacZ reporter at the Rosa26 locus (Rosa-Stop-lacZ), we genetically marked mammary epithelial cells in which the conditional Etv6-NTRK3 knockin allele were turned on, and followed them to the hyperplasia and tumor stages. We then sorted lacZ+ hyperplastic mammary epithelial cells and lacZ+ tumor epithelial cells and collected their expression profiles by Affymetrix mouse whole genome MOE430.2 chips. We also collected expression profiles from unfractionated mammary tumors (unsorted tumors) derived from the same mouse model and mammary glands from normal mice.
2008-06-16 | E-GEOD-9355 | biostudies-arrayexpress
Project description:We report a mouse model that recapitulates expression of the ETV6-NTRK3 (EN) fusion oncoprotein, the product of the t(12;15)(p13;q25) translocation characteristic of human secretory breast carcinoma. Activation of EN expression in mammary tissues by Whey acidic protein (Wap) promoter-driven Cre leads to fully penetrant, multifocal malignant breast cancer with short latency. We provide genetic evidence that committed bipotent or CD61+ luminal alveolar progenitors, are targets of tumorigenesis. Furthermore, EN transforms these otherwise transient progenitors through activation of the AP1 complex. Given increasing relevance of chromosomal translocations in epithelial cancers, such mice serve as a paradigm for the study of their genetic pathogenesis and cellular origins, and generation of novel preclinical models. In this study, we generated microarray expression profiling data from both genetically marked, FACS-sorted tumor epithelial cells and from unfractionated mammary tumors and normal mammary glands. By using gene set enrichment analysis (GSEA) on these data, we have identified the AP1 transcriptional complex as the major downstream effector of the ETV6-NTRK3 signaling. Keywords: genetic modification, cell type comparison
2007-12-14 | GSE9355 | GEO
Project description:We report a mouse model that recapitulates expression of the ETV6-NTRK3 (EN) fusion oncoprotein, the product of the t(12;15)(p13;q25) translocation characteristic of human secretory breast carcinoma. Activation of EN expression in mammary tissues by Whey acidic protein (Wap) promoter-driven Cre leads to fully penetrant, multifocal malignant breast cancer with short latency. We provide genetic evidence that committed bipotent or CD61+ luminal alveolar progenitors, are targets of tumorigenesis. Furthermore, EN transforms these otherwise transient progenitors through activation of the AP1 complex. To study the initial effects of ETV6-NTRK3 (EN) mediated transformation, we retrovirally transduced NIH 3T3 cells and generated microarray expression profiling data of EN transduced 3T3 cells as well as control 3T3 cells. Using gene set enrichment analysis (GSEA), we identified a signature involving the AP1 transcriptional complex in EN transduced 3T3 cells. Experiment Overall Design: We retrovirally transduced NIH 3T3 cells with either EN, or controls (either the empty vector or a kinase-dead version of EN with a mutation at the kinase domain of NTRK3). We then prepared total RNAs from these cells and collected microarray expression profiling data from them using Affymetrix mouse MOE430A chips.
2008-06-16 | E-GEOD-9354 | biostudies-arrayexpress
Project description:We report a mouse model that recapitulates expression of the ETV6-NTRK3 (EN) fusion oncoprotein, the product of the t(12;15)(p13;q25) translocation characteristic of human secretory breast carcinoma. Activation of EN expression in mammary tissues by Whey acidic protein (Wap) promoter-driven Cre leads to fully penetrant, multifocal malignant breast cancer with short latency. We provide genetic evidence that committed bipotent or CD61+ luminal alveolar progenitors, are targets of tumorigenesis. Furthermore, EN transforms these otherwise transient progenitors through activation of the AP1 complex. To study the initial effects of ETV6-NTRK3 (EN) mediated transformation, we retrovirally transduced NIH 3T3 cells and generated microarray expression profiling data of EN transduced 3T3 cells as well as control 3T3 cells. Using gene set enrichment analysis (GSEA), we identified a signature involving the AP1 transcriptional complex in EN transduced 3T3 cells. Keywords: genetic modification, cell type comparison
2007-12-14 | GSE9354 | GEO
Project description:We report a mouse model that recapitulates expression of the ETV6-NTRK3 (EN) fusion oncoprotein, the product of the t(12;15)(p13;q25) translocation characteristic of human secretory breast carcinoma. Activation of EN expression in mammary tissues by Whey acidic protein (Wap) promoter-driven Cre leads to fully penetrant, multifocal malignant breast cancer with short latency. We provide genetic evidence that committed bipotent or CD61+ luminal alveolar progenitors, are targets of tumorigenesis. Furthermore, EN transforms these otherwise transient progenitors through activation of the AP1 complex. Given increasing relevance of chromosomal translocations in epithelial cancers, such mice serve as a paradigm for the study of their genetic pathogenesis and cellular origins, and generation of novel preclinical models. We showed that forced expression of a dominant negative version of c-Jun (TAM67) in EN-transduced Eph4 mammary epithelial cells impairs their ability to form tumors in immunodeficient nude mice, thus provided validation that EN-initiated mammary tumorigenesis is largely mediated through the AP1 complex. Experiment Overall Design: To validate that EN-initiated mammary tumorigenesis is largely mediated through the AP1 complex, we generated EN-transduced Eph4 (EN-Eph4) mammary epithelial cells as well as EN-Eph4 cells co-expressing a dominant negative version of c-Jun (TAM67), and transplanted them into nude mice. We then isolated total RNAs from resulted tumors and collected their expression profiles using Affymetrix mouse MOE 430.2 chips.
2008-06-16 | E-GEOD-9353 | biostudies-arrayexpress
Project description:To model the effect of Pten loss on breast cancer, we deleted Pten using a floxed allele and the deleter lines MMTV-Cre(NLST), which targets stem/bi-potent progenitor cells, and WAP-Cre, which targets CD24-positive, pregnancy-identified stem cells/alveolar progenitors. Mammary tumors were detected in WAP-Cre:Ptenf/f females with a latency of 15.2 months. By 18 months, nearly all mice had succumbed to cancer. MMTV-Cre:Ptenf/f mice developed mammary tumors after a longer latency of 26.4 months and reduced penetrance (70%) compared to WAP-Cre:Ptenf/f mice. Tumors from both models were heterogeneous, consisting primarily of differentiated adenocarcinoma (adenomyoepithelioma; ~70%) and adenosquamous carcinoma (20-25%). In addition, a small fraction of tumors was classified as acinar and poorly differentiated adenocarcinoma (4-7%) and adenosarcoma (3-4%). To test the consequences of combined Pten and p53 gene mutation on breast cancer, we deleted both genes via MMTV-Cre or WAP-Cre. Kaplan-Meier tumor free survival curves revealed that WAP-Cre:Ptenf/f:p53f/f and MMTV-Cre:Ptenf/f:p53f/f females developed tumors with reduced latency of 11.3 and 9.8 months, compared with 15.2, 26.4, and 16.9 months for single-mutant WAP-Cre:Ptenf/f, MMTV-Cre:Ptenf/f or MMTV-Cre:p53f/f mice, respectively. In contrast to the heterogeneity of Pten tumors and small percentage of adenosarcomas in these mice, ~70% of Pten:p53 lesions were histologically classified as adeno-sacrcomatoid-like or mesenchymal-like breast cancer, with the rest exhibiting mixed mesenchymal plus adenocarcinomas and differentiated adenocarcinomas. The adeno-sacrcomatoid-like tumors expressed the mesenchymal markers vimentin, K5, SMA, N-cadherin and desmin but not ER, as well as islands of luminal-like K18 expressing cells surrounded by a layer of K14-positive cells. We used microarrays to detect differentially expressed genes in the Pten:p53 double-knock-out vs Pten or p53 single deletions Total RNA was extracted from tumors developed by double Trizol method and hybridized on Affymetrix microarrays.
2012-08-08 | E-GEOD-39955 | biostudies-arrayexpress
Project description:We report a mouse model that recapitulates expression of the ETV6-NTRK3 (EN) fusion oncoprotein, the product of the t(12;15)(p13;q25) translocation characteristic of human secretory breast carcinoma. Activation of EN expression in mammary tissues by Whey acidic protein (Wap) promoter-driven Cre leads to fully penetrant, multifocal malignant breast cancer with short latency. We provide genetic evidence that committed bipotent or CD61+ luminal alveolar progenitors, are targets of tumorigenesis. Furthermore, EN transforms these otherwise transient progenitors through activation of the AP1 complex. Given increasing relevance of chromosomal translocations in epithelial cancers, such mice serve as a paradigm for the study of their genetic pathogenesis and cellular origins, and generation of novel preclinical models. We showed that forced expression of a dominant negative version of c-Jun (TAM67) in EN-transduced Eph4 mammary epithelial cells impairs their ability to form tumors in immunodeficient nude mice, thus provided validation that EN-initiated mammary tumorigenesis is largely mediated through the AP1 complex. Keywords: genetic modification, cell type comparison
2007-12-14 | GSE9353 | GEO
Project description:To model the effect of Pten loss on breast cancer, we deleted Pten using a floxed allele and the deleter lines MMTV-Cre(NLST), which targets stem/bi-potent progenitor cells, and WAP-Cre, which targets CD24-positive, pregnancy-identified stem cells/alveolar progenitors. Mammary tumors were detected in WAP-Cre:Ptenf/f females with a latency of 15.2 months. By 18 months, nearly all mice had succumbed to cancer. MMTV-Cre:Ptenf/f mice developed mammary tumors after a longer latency of 26.4 months and reduced penetrance (70%) compared to WAP-Cre:Ptenf/f mice. Tumors from both models were heterogeneous, consisting primarily of differentiated adenocarcinoma (adenomyoepithelioma; ~70%) and adenosquamous carcinoma (20-25%). In addition, a small fraction of tumors was classified as acinar and poorly differentiated adenocarcinoma (4-7%) and adenosarcoma (3-4%). To test the consequences of combined Pten and p53 gene mutation on breast cancer, we deleted both genes via MMTV-Cre or WAP-Cre. Kaplan-Meier tumor free survival curves revealed that WAP-Cre:Ptenf/f:p53f/f and MMTV-Cre:Ptenf/f:p53f/f females developed tumors with reduced latency of 11.3 and 9.8 months, compared with 15.2, 26.4, and 16.9 months for single-mutant WAP-Cre:Ptenf/f, MMTV-Cre:Ptenf/f or MMTV-Cre:p53f/f mice, respectively. In contrast to the heterogeneity of Pten tumors and small percentage of adenosarcomas in these mice, ~70% of Pten:p53 lesions were histologically classified as adeno-sacrcomatoid-like or mesenchymal-like breast cancer, with the rest exhibiting mixed mesenchymal plus adenocarcinomas and differentiated adenocarcinomas. The adeno-sacrcomatoid-like tumors expressed the mesenchymal markers vimentin, K5, SMA, N-cadherin and desmin but not ER, as well as islands of luminal-like K18 expressing cells surrounded by a layer of K14-positive cells. We used microarrays to detect differentially expressed genes in the Pten:p53 double-knock-out vs Pten or p53 single deletions
2012-08-09 | GSE39955 | GEO
Project description:Many components of Wnt/β-catenin signaling pathway also play critical roles in mammary tumor development. To study the role of Apc in mammary tumorigensis, we introduced conditional Apc mutations specifically into two different mammary epithelial populations using K14-Cre (progenitor) and WAP-cre (lactaing luminal) transgenic mice. Only the K14-cre mediated Apc heterozygosity developed mammary adenocarcinomas demonstrating histological and molecular heterogeneity, suggesting the progenitor cell origin of these tumors. These tumors harbored truncation mutation in a very defined region in the remaining wild-type allele of Apc that would retain some down-regulating activity of β-catenin signaling. Our results suggest that not only the epithelial origin but also a certain Apc mutations are selected to achieve a specific level of β-catenin signaling optimal for mammary tumor development. Experiment Overall Design: We have compared 3 mammary tumors from K14-cre; ApcCKO/+ mice with 3 control mammary glands.
2009-02-21 | E-GEOD-14753 | biostudies-arrayexpress
Project description:For the largest class of human tumors, those of epithelial origin, little is known about their initiating genetic hits or cells of origin. Whether tissue stem cells or more committed progenitors are targets for transformation is also uncertain. Experience in hematopoietic malignancies and sarcomas teaches that recurrent chromosomal translocations represent initiating oncogenic events. To develop a system in which epithelial tumorigenesis can be assessed from the initial event to frank malignancy, we have generated mice that conditionally express the Etv6-NTRK3 (EN) fusion oncoprotein, the product of the t(12;15)(p13;q25) translocation characteristic of one form of human breast cancer. Activation of EN expression in mammary tissues by Whey acidic protein (Wap) promoter-driven Cre leads to fully penetrant, multifocal malignant breast cancer with short latency. We provide genetic evidence that committed, bipotent or CD61+ luminal alveolar progenitors, can be targets of tumorigenesis. Furthermore, EN transforms these otherwise transient progenitors through the AP1 complex. Our model supports the existence of an epithelial cell hierarchy in both normal mammary glands and malignancy. To our knowledge, this is the first murine model of human epithelial cancer based on a recurrent chromosomal translocation. Given increasing relevance of chromosomal translocations in epithelial cancers, such mice serve as a paradigm for the study of their genetic pathogenesis and cellular origins, and generation of novel preclinical models. Experiment Overall Design: Reference X Sample
2008-06-16 | E-GEOD-9343 | biostudies-arrayexpress