Overexpression of TSG101 causes cellular plasticity and development of adenosquamous mammary carcinoma
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ABSTRACT:
PROVIDER: PRJNA1129462 | ENA |
REPOSITORIES: ENA
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Project description:The mammalian Tumor Susceptibility Gene 101 (TSG101) encodes a protein with diverse functions that control the proliferation and survival of cells, but its role in malignant transformation has remained enigmatic. To study the pro-tumorigenic functions of TSG101, we developed a transgenic mouse model that expresses exogenous TSG101 along with a luciferase reporter in a ligand-controlled manner in the mammary gland epithelium. Females overexpressing TSG101 develop ductal hyperplasia, adenomyoepitheliomas, and palpable adenosquamous carcinomas at an average latency of aproximately 10 months. These metaplastic mammary tumors are comprised of transforming basal and luminal epithelial cells, and using a GFP reporter strain to monitor the transgene activation on the single-cell level, we determined that the epithelial heterogeneity within transforming ducts and carcinomas was the result of cellular plasticity wihtin the luminal epithelium. On the molecular level, TSG101-induced mammary tumors are triple-negative and exhibit gene expression signatures of Wnt and inflammatory cytokine signaling, which are key regulators of epithelial cell fate. The ligand-controlled downregulation of exogenous TSG101 in established carcinomas led to tumor regression. We demonstrated that the TSG101-mediated activation of PI3K/AKT signaling as well as upregulation of Cyclin D1 and MDM2 are dependent on the perpetual expression of the oncoprotein. The collective findings of this study provide in vivo evidence that TSG101 has pro-tumorigenic properties that extend to cancer progression and maintenance, suggesting that this protein could be a rational molecular target to prevent and treat a subset of mammary tumors.
2025-07-16 | GSE271036 | GEO
Project description:The JNK pathway has been implicated in breast cancer, both from human tumor sequencing studies and from mouse models. To see if JNK deletion is able to form tumors in mice, we crossed Mapk8 and Mapk9 conditional animals with the WAP-Cre expressing mouse to specifically delete JNK in luminal epithelial cells of the breast. We found that JNK suppresses tumors and that the loss of JNK leads to adenosquamous carcinoma formation. To understand the role of JNK in the mammary epithelium, we performed RNA sequencing and analyzed gene expression from tumor-derived cell lines. Several pathways were perturbed in the carcinoma cell lines. Our results demonstrate that loss of JNK alone is sufficient to cause tumor formation and they reveal a gene signature of adenosquamous tumors that can help in better understanding and treating the disease.
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Project description:Sustained proliferation and aberrant cellular plasticity are the hallmarks of breast premalignancy, yet the mechanisms driving this process remain unclear. Using CRISPR knockout screens, we systematically characterized the regulators of cellular fitness in the normal mammary epithelium. We found that loss of RNA methyltransferase METTL3 initiates mammary epithelial proliferation and reprograms gene expression, which depends on its catalytic activity. Single-cell analysis in normal breast organoids revealed that METTL3 ablation causes disruption of the mammary cellular hierarchy through increased aberrant luminal differentiation. Mechanically, METTL3 loss reduces the RNA m6A modification of transcribed transposable elements leading to their increased expression and upregulating interferon-STAT signaling. This inflammatory response leads to the crosstalk between STAT and GATA3 transcription factors, resulting in transcriptional activation of luminal genes in the mammary epithelium. These findings identify a cell-intrinsic epigenetic loop contributing to mammary epithelial plasticity and highlight a potential role of METTL3-dependent m6A modification during neoplastic transformation.
2025-11-01 | GSE280918 | GEO
Project description:Sustained proliferation and aberrant cellular plasticity are the hallmarks of breast premalignancy, yet the mechanisms driving this process remain unclear. Using CRISPR knockout screens, we systematically characterized the regulators of cellular fitness in the normal mammary epithelium. We found that loss of RNA methyltransferase METTL3 initiates mammary epithelial proliferation and reprograms gene expression, which depends on its catalytic activity. Single-cell analysis in normal breast organoids revealed that METTL3 ablation causes disruption of the mammary cellular hierarchy through increased aberrant luminal differentiation. Mechanically, METTL3 loss reduces the RNA m6A modification of transcribed transposable elements leading to their increased expression and upregulating interferon-STAT signaling. This inflammatory response leads to the crosstalk between STAT and GATA3 transcription factors, resulting in transcriptional activation of luminal genes in the mammary epithelium. These findings identify a cell-intrinsic epigenetic loop contributing to mammary epithelial plasticity and highlight a potential role of METTL3-dependent m6A modification during neoplastic transformation.
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Project description:Sustained proliferation and aberrant cellular plasticity are the hallmarks of breast premalignancy, yet the mechanisms driving this process remain unclear. Using CRISPR knockout screens, we systematically characterized the regulators of cellular fitness in the normal mammary epithelium. We found that loss of RNA methyltransferase METTL3 initiates mammary epithelial proliferation and reprograms gene expression, which depends on its catalytic activity. Single-cell analysis in normal breast organoids revealed that METTL3 ablation causes disruption of the mammary cellular hierarchy through increased aberrant luminal differentiation. Mechanically, METTL3 loss reduces the RNA m6A modification of transcribed transposable elements leading to their increased expression and upregulating interferon-STAT signaling. This inflammatory response leads to the crosstalk between STAT and GATA3 transcription factors, resulting in transcriptional activation of luminal genes in the mammary epithelium. These findings identify a cell-intrinsic epigenetic loop contributing to mammary epithelial plasticity and highlight a potential role of METTL3-dependent m6A modification during neoplastic transformation.
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Project description:Sustained proliferation and aberrant cellular plasticity are the hallmarks of breast premalignancy, yet the mechanisms driving this process remain unclear. Using CRISPR knockout screens, we systematically characterized the regulators of cellular fitness in the normal mammary epithelium. We found that loss of RNA methyltransferase METTL3 initiates mammary epithelial proliferation and reprograms gene expression, which depends on its catalytic activity. Single-cell analysis in normal breast organoids revealed that METTL3 ablation causes disruption of the mammary cellular hierarchy through increased aberrant luminal differentiation. Mechanically, METTL3 loss reduces the RNA m6A modification of transcribed transposable elements leading to their increased expression and upregulating interferon-STAT signaling. This inflammatory response leads to the crosstalk between STAT and GATA3 transcription factors, resulting in transcriptional activation of luminal genes in the mammary epithelium. These findings identify a cell-intrinsic epigenetic loop contributing to mammary epithelial plasticity and highlight a potential role of METTL3-dependent m6A modification during neoplastic transformation.
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Project description:Overexpression of ECD in mammary gland promotes mammary tumorigenesis. To determine the plausible mechanism of how ECD contributes the oncogenesis, we performed RNAseq analysis of three independent control mice mammary glands (6 months old) and four independent ECD transgenic mammary tumors. Out of these four tumors, T1a and T1b were adenosquamous carcinoma type, T3 was Spindle cell carcinoma type and T4 was papillary carcinoma. RNA was isolated from the respective samples and RNAseq was performed.
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Project description:Proximal proteomics of epithelial cell plasticity in tumorigenesis
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Project description:The aberrant overexpression of mucin 1 (MUC1) and human epidermal growth factor receptor 2 (HER2) are often observed in breast cancer. However, the role of concomitant of MUC1/HERR2 in the development of breast cancer has not been fully illustrated. Following analysis public microarray datasets that revealed a correlation of double positive of MUC1 and HER2 to a worse clinical outcome, we generated a mouse model overexpressing both Her2 and MUC1 cytoplasmic domain (MUC1-CD) to investigate their interaction in mammary carcinogenesis. Coexpression of Her2 and MUC1-CD confers growth advantage and promotes the development of spontaneous mammary tumors. Genomic analysis uncovers that enforced expression of MUC1-CD and Her2 induces mammary tumor lineage plasticity which is supported by gene reprogramming and mammary stem cell enrichment. With gain- and loss-of function strategies, we show that coexpression of Her2 and MUC1-CD was associated with down-regulation of TCA cycle genes in tumors. Importantly, the reduction of TCA cycle genes induced by MUC1-CD is is significantly connected to the poor prognosis in HER2+ breast cancer patients. In addition, MUC1 augments Her2 signaling pathway by inducing Her2/Egfr dimerization. These findings collectively demonstrate the vital role of MUC1-CD/Her2 collaboration in shaping mammary tumor landscape and highlight the prognostic and therapeutic implication of MUC1 in patients with Her2+ breast cancer.
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