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1.
Nat Commun ; 12(1): 5238, 2021 09 02.
Article in English | MEDLINE | ID: mdl-34475389

ABSTRACT

The most common events in breast cancer (BC) involve chromosome arm losses and gains. Here we describe identification of 1089 gene-centric common insertion sites (gCIS) from transposon-based screens in 8 mouse models of BC. Some gCIS are driver-specific, others driver non-specific, and still others associated with tumor histology. Processes affected by driver-specific and histology-specific mutations include well-known cancer pathways. Driver non-specific gCIS target the Mediator complex, Ca++ signaling, Cyclin D turnover, RNA-metabolism among other processes. Most gCIS show single allele disruption and many map to genomic regions showing high-frequency hemizygous loss in human BC. Two gCIS, Nf1 and Trps1, show synthetic haploinsufficient tumor suppressor activity. Many gCIS act on the same pathway responsible for tumor initiation, thereby selecting and sculpting just enough and just right signaling. These data highlight ~1000 genes with predicted conditional haploinsufficient tumor suppressor function and the potential to promote chromosome arm loss in BC.


Subject(s)
Breast Neoplasms/genetics , Loss of Heterozygosity/genetics , Animals , Breast Neoplasms/pathology , Cell Transformation, Neoplastic , DNA Transposable Elements/genetics , Female , Genes, Tumor Suppressor , Humans , Mice , Mutagenesis, Insertional , Neoplasms, Experimental , Signal Transduction
2.
Cancer Res ; 77(6): 1357-1368, 2017 03 15.
Article in English | MEDLINE | ID: mdl-28108518

ABSTRACT

RAS genes are mutated in 20% of human tumors, but these mutations are very rare in breast cancer. Here, we used a mouse model to generate tumors upon activation of a mutagenic T2Onc2 transposon via expression of a transposase driven by the keratin K5 promoter in a p53+/- background. These animals mainly developed mammary tumors, most of which had transposon insertions in one of two RASGAP genes, neurofibromin1 (Nf1) and RAS p21 protein activator (Rasa1). Immunohistochemical analysis of a collection of human breast tumors confirmed that low expression of RASA1 is frequent in basal (triple-negative) and estrogen receptor negative tumors. Bioinformatic analysis of human breast tumors in The Cancer Genome Atlas database showed that although RASA1 mutations are rare, allelic loss is frequent, particularly in basal tumors (80%) and in association with TP53 mutation. Inactivation of RASA1 in MCF10A cells resulted in the appearance of a malignant phenotype in the context of mutated p53. Our results suggest that alterations in the Ras pathway due to the loss of negative regulators of RAS may be a common event in basal breast cancer. Cancer Res; 77(6); 1357-68. ©2017 AACR.


Subject(s)
Biomarkers, Tumor/metabolism , DNA Transposable Elements/genetics , Transposases/physiology , Triple Negative Breast Neoplasms/pathology , Tumor Suppressor Protein p53/physiology , p120 GTPase Activating Protein/metabolism , Animals , Apoptosis , Biomarkers, Tumor/genetics , Cell Proliferation , Cells, Cultured , Female , Humans , Mice , Mice, Transgenic , Neoplasm Staging , Prognosis , Triple Negative Breast Neoplasms/genetics , Triple Negative Breast Neoplasms/metabolism , p120 GTPase Activating Protein/genetics
3.
J Invest Dermatol ; 133(7): 1870-8, 2013 Jul.
Article in English | MEDLINE | ID: mdl-23426135

ABSTRACT

CYLD is a tumor-suppressor gene mutated in the skin appendage tumors cylindromas, trichoepitheliomas, and spiradenomas. We have performed in vivo metastasis assays in nude mice and found that the loss of the deubiquitinase function of CYLD in squamous cell carcinoma (SCC) cells greatly enhances the lung metastatic capability of these cells. These metastases showed several characteristics that make them distinguishable from those carrying a functional CYLD, such as robust angiogenesis, increased expression of tumor malignancy markers of SCCs, and a decrease in the expression of the suppressor of metastasis Maspin. Restoration of Maspin expression in the epidermal SCC cells defective in CYLD deubiquitination function significantly reduces their ability to form metastases, thereby suggesting that the decrease in the levels of Maspin expression plays an important role in the acquisition of metastatic potential of these cells. In addition, we have characterized Maspin downregulation in cylindromas, trichoepitheliomas, and spiradenomas carrying functional inactivating mutations of CYLD, also providing an evidence of the correlation between impaired CYLD function and Maspin decreased expression in vivo in human tumors.


Subject(s)
Carcinoma, Squamous Cell/secondary , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/pathology , Cysteine Endopeptidases/genetics , Lung Neoplasms/secondary , Mutation/genetics , Skin Neoplasms/pathology , Animals , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/metabolism , Cysteine Endopeptidases/metabolism , Deubiquitinating Enzyme CYLD , Disease Models, Animal , Keratin-13/genetics , Keratin-13/metabolism , Keratin-8/genetics , Keratin-8/metabolism , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Mice , Mice, Nude , Neovascularization, Pathologic/genetics , Serpins/genetics , Serpins/metabolism , Skin/metabolism , Skin/pathology , Skin Neoplasms/genetics , Skin Neoplasms/metabolism , Snail Family Transcription Factors , Transcription Factors/genetics , Transcription Factors/metabolism
4.
J Invest Dermatol ; 133(1): 239-48, 2013 Jan.
Article in English | MEDLINE | ID: mdl-22832494

ABSTRACT

Nonmelanoma skin cancer (NMSC) is by far the most frequent type of cancer in humans. NMSC includes several types of malignancies with different clinical outcomes, the most frequent being basal and squamous cell carcinomas. We have used the Sleeping Beauty transposon/transposase system to identify somatic mutations associated with NMSC. Transgenic mice bearing multiple copies of a mutagenic Sleeping Beauty transposon T2Onc2 and expressing the SB11 transposase under the transcriptional control of regulatory elements from the keratin K5 promoter were treated with TPA, either in wild-type or Ha-ras mutated backgrounds. After several weeks of treatment, mice with transposition developed more malignant tumors with decreased latency compared with control mice. Transposon/transposase animals also developed basal cell carcinomas. Genetic analysis of the transposon integration sites in the tumors identified several genes recurrently mutated in different tumor samples, which may represent novel candidate cancer genes. We observed alterations in the expression levels of some of these genes in human tumors. Our results show that inactivating mutations in Notch1 and Nsd1, among others, may have an important role in skin carcinogenesis.


Subject(s)
Carcinoma, Basal Cell/genetics , Carcinoma, Squamous Cell/genetics , Cell Transformation, Neoplastic/genetics , DNA Transposable Elements/genetics , Mutation , Skin Neoplasms/genetics , Animals , Carcinogens/toxicity , Carcinoma, Basal Cell/pathology , Carcinoma, Squamous Cell/pathology , Carrier Proteins/genetics , DNA Mutational Analysis/methods , Genes, ras/genetics , Histone Methyltransferases , Histone-Lysine N-Methyltransferase , Humans , Intracellular Signaling Peptides and Proteins/genetics , Keratin-15 , Keratin-5/genetics , Mice , Mice, Inbred C57BL , Mice, Inbred DBA , Mice, Transgenic , Nuclear Proteins/genetics , Promoter Regions, Genetic , Receptor, Notch1/genetics , Skin Neoplasms/pathology , Tetradecanoylphorbol Acetate/toxicity , Transposases/genetics
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