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Microarray expression profiles of mammary tumors developed in Wap-Cre;Etv6-NTRK3 mice

ABSTRACT: 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

ORGANISM(S): Mus musculus

PROVIDER: GSE9355 | GEO | 2007/12/14

SECONDARY ACCESSION(S): PRJNA103049

REPOSITORIES: GEO

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Transcription profiling of mouse mammary tumours developed in Wap-Cre;Etv6-NTRK3 mice

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

ETV6-NTRK3 fusion oncoprotein transduces NIH 3T3 cells

2007-12-14 | GSE9354 | GEO

Transcription profiling of mouse model that recapitulates the ETV6-NTRK3 fusion oncoprotein the product of the t(12;15)(p13;q25) translocation characteristic of human secretory breast carcinoma

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

Transcription profiling of mouse model for ETV6-NTRK3 (EN) fusion oncoprotein expresson

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

The effect of dominant negative c-Jun, TAM67, on tumorigenesis of ETV6-NTRK3 transduced Eph4 cells

2007-12-14 | GSE9353 | GEO

Transcription profiling of mammary tissues from mouse model of breast cancer conditionally expressing Etv6-NTRK3 (EN) fusion oncoprotein, the product of the t(12;15)(p13;q25) translocation

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

ETV6-NTRK3 fusion oncogene initiates breast cancer from committed alveolar progenitors via activation of AP1 complex

2008-04-07 | GSE9343 | GEO

NTRK3 kinase fusions in melanocytic tumors

Project description:We analyzed the copy number profiles of clinical samples of diagnostically difficult melanocytic tumors. Of 1202 cases, 22 cases demonstrated relative gain of the 5' portion of NTRK3. We further performed DNA or RNA sequencing on 12 of these cases and identified ETV6-NTRK3, MYO5A-NTRK3 and MYH9-NTRK3 fusions in the 8 cases in this cohort. Analysis of genomic copy number of melanocytic tumors versus commericial pooled normal control.

2017-05-18 | GSE81625 | GEO

Examining the Impact of ETV6-NTRK3 Oncogenic Gene Fusions on Molecular and Signaling Pathway Alterations

Project description:Oncofusions form when chromosomal translocations join two genes to create a protein with oncogenic properties. The oncogenic ETV6-NTRK3 (EN) gene fusion joins the sterile alpha domain of the ETV6 transcription factor with the tyrosine kinase domain of the neurotrophin-3 receptor NTRK3. Four EN variants with alternating break points have since been detected in a wide range of human cancers. To provide insight into EN oncogenesis, we employed a proximity labeling mass spectrometry approach to define the molecular context of the fusions. We identify 237 high-confidence interactors, which link EN fusions to several key signaling pathways, including ERBB, Insulin and JAK/STAT. We then assess the effects of EN variants on these pathways, and show that the pan NTRK inhibitor selitrectinib (LOXO-195) inhibits the oncogenic activity of EN2, the most common variant. This systems-level analysis of defines the molecular framework in which EN oncofusions operate to promote cancer.

2023-01-13 | MSV000091061 | MassIVE

Anti-Tumor Activity of Entrectinib, a Pan-TRK, ROS1 and ALK Inhibitor, in ETV6-NTRK3-Positive Acute Myeloid Leukemia

Project description:Activation of TRK family tyrosine kinases by chromosomal rearrangement has been shown to drive a wide range of solid tumors and hematologic malignancies. TRK fusions are actionable targets as evidenced by recent clinical trial results in solid tumors. Entrectinib (RXDX-101) is an investigational, orally available, CNS-active, highly potent and selective kinase inhibitor with low nanomolar potency against TRKA/B/C, ROS1 and ALK kinase activities. Here, we demonstrate that TRK kinase inhibition by entrectinib selectively targets preclinical models of TRK fusion-driven hematologic malignancies. In acute myeloid leukemia (AML) cell lines with endogenous expression of the ETV6-NTRK3 fusion gene, entrectinib treatment blocked cell proliferation and induced apoptotic cell death in vitro with sub-nanomolar IC50 values. Phosphorylation of the ETV6-TRKC fusion protein, as well as phosphorylation of known TRKC downstream signaling effectors, was inhibited by entrectinib treatment in a dose-dependent manner. Sensitivity to entrectinib was dependent on expression of the ETV6-TRKC fusion protein. In xenograft models, entrectinib treatment at clinically relevant doses resulted in tumor regression, which was accompanied by elimination of residual cancer cells from the bone marrow. Our preclinical data demonstrate the potential of entrectinib as an effective treatment for patients with TRK fusion-driven AML and provide rationale for the clinical development of entrectinib in molecularly defined hematologic malignancies.

2018-07-05 | GSE100885 | GEO

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