Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA335319 | ENA |
REPOSITORIES: ENA
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Project description:We show that macrophages are recruited to ductal hyperplasias that have a high tumor-forming potential where they are differentiated and polarized toward a tumor-promoting phenotype. These studies suggest that therapeutic targeting of tumor-promoting macrophages may not only be an effective strategy to block tumor progression and metastasis, but may also have critical implications for breast cancer prevention. To investigate mechanisms that drive tumorigenesis in early breast cancer progression, we employed a transplantable model of preneoplastic progression. Transplantation of p53-null mammary epithelial cells into the cleared mammary fad pads of syngeneic wildtype mice led to the formation of several premalignant lines that histologically and genetically recapitulated the various subtypes of human breast cancer. Two of these lines, PN1a and PN1b, were derived from contralateral outgrowths from the same mouse, and tissue from these outgrowths was serially transplanted for over 10 generations to confirm stability. At 16 weeks post-transplantation, PN1a lesions develop a poorly differentiated, lobuloalveolar morphology with multifocal regions of atypical cells in solid nests, while PN1b lesions remain low grade, ductal hyperplasia.
2017-06-04 | GSE84828 | GEO
Project description:The tumor suppressor gene p53 is frequently mutated in human breast cancer and is a marker for poor prognosis and resistance to chemotherapy. Transplantation of p53-null mouse mammary epithelium into syngeneic wild-type mice leads to normal mammary gland development followed by spontaneous mammary tumors that recapitulate many of the phenotypic, molecular, and genetic features of human breast cancer. Using this genetically engineered mouse model, we have examined the molecular mechanisms underlying tamoxifen-dependent tumor prevention. To determine whether the changes observed in the ERα cistrome after tamoxifen exposure are reflected in changes in estrogen responsive gene signatures in p53-null mammary epithelial cells (MECs), we performed global gene expression analysis by microarray profiling of MECs isolated from control and tamoxifen-exposed mice 4 weeks after tamoxifen withdrawal and treated with E2 for 8h. We identified 245 differentially regulated genes (P<0.01 and FC>1.4). Of these, 177 genes (72%) were persistently upregulated and 68 genes (28%) were persistently downregulated after transient exposure to tamoxifen. These results indicate that transient exposure to tamoxifen leads to lasting intrinsic changes in gene expression profiles of p53-null mammary epithelial cells that persist after tamoxifen withdrawal.
2018-04-17 | GSE77948 | GEO
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
2011-08-14 | E-GEOD-27101 | biostudies-arrayexpress
Project description:In human breast cancer, mutations in the p53 gene are associated with poor prognosis, suggesting a mutant p53 “gain of function”. To study this phenomenon, we co-expressed mutant p53R270H in mice in which SV40 early proteins initiate the development of mammary adenocarcinomas in descendants of mammary epithelial cells that survived involution (WAPT-mice). This model allows the characterization of mammary carcinomas that developed in the absence or presence of mutant p53, while the endogenous wild-type p53 is functionallycompromised. Co-expression of mutant p53 significantly aggravated the phenotype of bitransgenic mice, as evidenced by a higher tumor incidence, a worse clinical staging and histological grading, as well as an enhanced invasiveness of the tumors, and more frequent pulmonary metastasis. Our data indicate that mutant p53 does not exert this effect by increasing genomic instability. On the contrary, lower grade tumors in WAP-T mice generally accumulated more amplifications of pro-survival genes than the corresponding tumors in bitransgenic animals, suggesting that mutant p53 can compensate for such genetic alterations by alternative mechanisms, possibly by its transcriptional activities, and thereby facilitate tumor formation. As a common feature and associated with their enhanced invasiveness, high grade tumors showed high level amplification of the Met-locus. Keywords: mutant p53, SV40 early proteins, tumor progression, tumor grade, tumor stage, mammary carcinoma, animal model, Met
2007-12-31 | GSE7135 | GEO
Project description:RNAseq expression of p53-null and p53-null/PLK2-null mammary tumors
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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.
2011-08-15 | GSE27101 | GEO
Project description:p53 is a known tumor suppressor. We have found that stromal p53 regulates breast cancer development, the immune landscape, and survival in an oncogene specific manner when comparing the epithelial oncogenes ErbB2 and KrasG12D In this dataset, we have evaluated mammary epithelia from mice with and without epithelial KrasG12D and with and without stromal p53 deletion. We have also evaluated mammary fibroblasts from mice with and without epithelial KrasG12D and with and without stromal p53 deletion.
2022-05-01 | GSE201935 | GEO
Project description:Biallelic loss of cyclin-dependent kinase 12 (CDK12) defines a unique molecular subtype of metastatic castration resistant prostate cancer (mCRPC). It remains unclear, however, whether CDK12 loss per se is sufficient to drive prostate cancer development—either alone, or in the context of other genetic alterations—and whether CDK12-mutant tumors exhibit sensitivity to specific pharmacotherapies. Here, we demonstrate that tissue-specific Cdk12 ablation is sufficient to induce preneoplastic lesions in the mouse prostate. Allograft-based CRISPR screening demonstrated that Cdk12 loss is positively associated with p53 inactivation, but negatively associated with Pten inactivation—similar to what is seen in human mCRPC. Consistent with this, ablation of Cdk12 in prostate organoids with concurrent p53 loss promotes their proliferation and ability to form tumors in mice, while Cdk12 knockout in the Pten-null prostate cancer mouse model abrogates tumor growth. Bigenic CDK12 and p53 loss allografts represent a new syngeneic model for the study of prostate cancer. Cdk12-null organoids (either with or without p53 co-ablation) and patient-derived xenografts from tumors with CDK12 inactivation are highly sensitive to inhibition or degradation of its paralog kinase, CDK13. Together, these data identify CDK12 as a bona fide tumor suppressor gene with impact on tumor progression and paralog-based synthetic lethality is a promising strategy for treating CDK12 mutant mCRPC.
2024-04-17 | GSE254388 | GEO
Project description:Biallelic loss of cyclin-dependent kinase 12 (CDK12) defines a unique molecular subtype of metastatic castration resistant prostate cancer (mCRPC). It remains unclear, however, whether CDK12 loss per se is sufficient to drive prostate cancer development—either alone, or in the context of other genetic alterations—and whether CDK12-mutant tumors exhibit sensitivity to specific pharmacotherapies. Here, we demonstrate that tissue-specific Cdk12 ablation is sufficient to induce preneoplastic lesions in the mouse prostate. Allograft-based CRISPR screening demonstrated that Cdk12 loss is positively associated with p53 inactivation, but negatively associated with Pten inactivation—similar to what is seen in human mCRPC. Consistent with this, ablation of Cdk12 in prostate organoids with concurrent p53 loss promotes their proliferation and ability to form tumors in mice, while Cdk12 knockout in the Pten-null prostate cancer mouse model abrogates tumor growth. Bigenic CDK12 and p53 loss allografts represent a new syngeneic model for the study of prostate cancer. Cdk12-null organoids (either with or without p53 co-ablation) and patient-derived xenografts from tumors with CDK12 inactivation are highly sensitive to inhibition or degradation of its paralog kinase, CDK13. Together, these data identify CDK12 as a bona fide tumor suppressor gene with impact on tumor progression and paralog-based synthetic lethality is a promising strategy for treating CDK12 mutant mCRPC.
2024-04-17 | GSE254387 | GEO
Project description:This study examined the effect of mutant PIK3CAH1047R expression in mammary subsets of preneoplastic mammary glands from Lgr5-creERT2/PIK3CA H1047R mice
2015-08-12 | GSE59870 | GEO