MUC1 triggers lineage plasticity of Her2 positive mammary tumor
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ABSTRACT:
PROVIDER: PRJNA814266 | ENA |
REPOSITORIES: ENA
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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.
2022-03-10 | GSE198239 | GEO
Project description:Neuroendocrine prostate cancer (NEPC) is a highly aggressive malignancy of increasing prevalence with an unmet need for targeted therapeutic approaches. The oncogenic MUC1-C protein is overexpressed in castration-resistant prostate cancer (CRPC) and NEPC; however, there is no known role for MUC1-C in driving lineage plasticity to these advanced PC phenotypes. The present studies demonstrate that upregulation of MUC1-C in androgen-independent (AI) PC cells suppresses androgen receptor (AR) axis signaling and induces the neural BRN2 transcription factor by a previously unrecognized MYC-mediated mechanism. MUC1-C activates the BRN2 pathway in association with induction of MYCN, EZH2 and NE differentiation markers (ASCL1, AURKA and SYP), which are linked to NEPC progression. We also show that MUC1-C suppresses the p53 pathway, induces the Yamanaka pluripotency factors (OCT4, SOX2, KLF4 and MYC) and drives stemness. Of potential clinical relevance, targeting MUC1-C decreases PC self-renewal capacity and tumorigenicity, supporting the treatment of CRPC and NEPC with agents directed against this oncoprotein. These findings and the demonstration that MUC1-C is upregulated and associated with suppression of AR signaling, and increases in BRN2 expression and the NEPC score in PC tissues highlight the unanticipated importance of MUC1-C as a master effector of lineage plasticity in progression to advanced PC with NE features.
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Project description:Mucin 1 (MUC1) is a transmembrane mucin expressed at the apical surface of epithelial cells at different mucosal surfaces including breast and intestine. The MUC1 extracellular domain contains a variable number of tandem repeats (VNTR) of 20 amino acids, which are heavily O-linked glycosylated. Monoclonal antibodies against the MUC1 VNTR can be powerful tools because of their multiplicity of binding and possible applications in the diagnosis and treatment of MUC1-expressing cancers. One such antibody is the hybridoma mouse monoclonal 139H2 which is also widely used as a research tool to study non-cancer MUC1. Here we report direct mass spectrometry-based sequencing of hybridoma-derived 139H2 IgG, which enabled reverse engineering of a recombinant 139H2.
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Project description:The MUC1-C protein evolved in mammals for adaptation of barrier tissues to loss of homeostasis. Prolonged activation of MUC1-C in settings of chronic inflammation promotes lineage plasticity, epigenetic reprogramming and the cancer stem cell (CSC) state. The effects of MUC1-C on the metabolism of CSCs remain unexplored. We used single cell RNA sequencing (scRNA-seq) to analyze the diversity of BT-549 spheroid cultures with and without knockdown of MUC1 to examine the effects of MUC1 on CSC renewal and metbolic states.
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Project description:The NuRD chromatin remodeling and deacetylation complex, which includes MTA1, MBD3, CHD4 and HDAC1 among other components, is of importance for development and cancer progression. The oncogenic MUC1-C protein activates EZH2 and BMI1 in the epigenetic reprogramming of triple-negative breast cancer (TNBC) cells. However, there is no known link between MUC1-C and chromatin remodeling complexes. The present studies demonstrate that MUC1-C binds directly to the MYC HLH/LZ domain. In turn, we identified a previously unrecognized MUC1-C®MYC pathway that regulates the NuRD complex. We show that MUC1-C/MYC complexes selectively activate the MTA1 and MBD3 genes and posttranscriptionally induce CHD4 expression in basal- and not luminal-type BC cells. The results further show that MUC1-C forms complexes with these NuRD components on the ESR1 promoter. In this way, silencing MUC1-C (i) decreased MTA1/MBD3/CHD4/HDAC1 occupancy and increased H3K27 acetylation on the ESR1 promoter, and (ii) induced ESR1 expression and downstream estrogen response pathways. We also demonstrate that targeting MUC1-C and these NuRD components induces expression of FOXA1, GATA3 and other markers associated with the luminal phenotype. These findings and results from gain-of-function studies support a model in which MUC1-C activates the NuRD complex in driving luminal®basal dedifferentiation and plasticity of TNBC cells.
2020-03-05 | GSE134147 | GEO
Project description:Goal of study: To determine differentially expressed genes with potential roles in tolerance and immunity in MUC1-immunized WT and MUC1.Tg mice WT (C57Bl/6) and MUC1.Tg mice were immunized (i.v.) with dendritic cells loaded with sythetic, human MUC1 peptide. At 24h and 72h splenic RNA from vaccination groups (n=3) was pooled and microarray performed.
2013-01-16 | E-GEOD-43503 | biostudies-arrayexpress
Project description:Androgen receptor positive prostate cancer (PC), castration resistant prostate cancer (CRPC) and neuroendocrine prostate cancer (NEPC) represent a spectrum of malignancies that invariably become resistant to treatment with targeted and cytotoxic agents. There is no known common pathway responsible for these pleotropic mechanisms of resistance. The MUC1 gene is aberrantly expressed in CRPC and NEPC in association with poor clinical outcomes. The present results demonstrate that the oncogenic MUC1-C protein is necessary for resistance of (i) PC cells to enzalutamide (ENZ), and (ii) CRPC and NEPC cells to docetaxel (DTX). We show that MUC1-C-mediated ENZ and DTX resistance is conferred by upregulation of aerobic glycolysis and suppression of reactive oxygen species (ROS) necessary for self-renewal capacity. Common dependence of these drug-resistant phenotypes on MUC1-C for the cancer stem cell (CSC) state thus identified a potential new target for their treatment. cIn this context, we further demonstrate that targeting MUC1-C with an antibody-drug conjugate (ADC) is highly effective in suppressing (i) self-renewal of drug-resistant CRPC and NEPC CSCs and (ii) growth of t-NEPC tumor xenografts derived from drug-resistant cells and a patient with refractory disease. These findings reveal a shared MUC1-C-dependent pathway in drug-resistant CRPC and NEPC progression and identify MUC1-C as a target for their treatment with an ADC.
2025-02-16 | GSE289308 | GEO
Project description:The MUC1-C protein evolved in mammals for adaptation of barrier tissues to loss of homeostasis. Prolonged activation of MUC1-C in settings of chronic inflammation promotes lineage plasticity, epigenetic reprogramming and the cancer stem cell (CSC) state. The effects of MUC1-C on the metabolism of CSCs remain unexplored. The present studies performed on purified populations of triple-negative breast cancer (TNBC) CSCs demonstrate that MUC1-C integrates the capacity for self-renewal with the activation of aerobic glycolysis. We show that MUC1-C is essential for (i) CSC mammosphere formation and tumorigenicity and (ii) activation of GLUT1, HK2 and other glycolytic genes. We further show that MUC1-C activates nuclear genes that encode components of mitochondrial Complexes II-V of the electron transfer chain (ETC). Of importance, MUC1-C also represses mitochondrial DNA (mtDNA) genes encoding components of Complexes I-V. The observed involvement of MUC1-C in the suppression of mtDNA genes is explained by MUC1-C-mediated (i) downregulation of the mitochondrial transcription factor A (TFAM), which is required for mtDNA transcription, and (ii) induction of the mitochondrial transcription termination factor 3 (mTERF3). In support of this pathway to suppress mitochondrial ROS production, targeting MUC1-C increases (i) mtDNA gene transcription, (ii) superoxide levels and (iii) loss of self-renewal capacity. These findings indicate that MUC1-C regulates CSC self-renewal and redox balance by integrating activation of glycolysis with suppression of oxidative phosphorylation.
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