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Project description:The potent MYC oncoprotein is deregulated in many human cancers, including breast carcinoma, and is associated with aggressive disease. To understand the mechanisms and vulnerabilities of MYC-driven breast cancer, we have generated an in vivo model that mimics human disease in response to MYC deregulation. MCF10A cells ectopically expressing a common breast cancer mutation in the PI3 kinase pathway (PIK3CAH1047R) lead to the development of organized acinar structures in mice. However, expressing both PIK3CAH1047R and deregulated-MYC lead to the development of invasive ductal carcinoma, thus creating a model in which a MYC-dependent normal-to-tumour switch occurs in vivo. These MYC-driven tumours exhibit classic hallmarks of human breast cancer at both the pathological and molecular levels. Moreover, tumour growth is dependent upon sustained deregulated MYC expression, further demonstrating addiction to this potent oncogene and regulator of gene transcription. We therefore provide a MYC-dependent model of breast cancer which can be assayed for in vivo tumour initiation, proliferation, and transformation from normal breast acini into invasive breast carcinoma. Taken together, we anticipate that this novel MYC-driven transformation model will be a useful research tool to both better understand MYC’s oncogenic function and identify therapeutic vulnerabilities.
2019-07-25 | GSE130513 | GEO
Project description:We recently established the ERK-dependent transcriptome and phosphoproteome in KRAS-mutant pancreatic ductal adenocarcinoma (PDAC). Of 1,718 ERK-dependent genes, 143 encode transcription factors. Of 2,123 ERK-dependent phosphoproteins, 98 are transcription factors. Despite this complexity, we observed that genetic suppression of the MYC transcription factor alone phenocopied KRAS suppression in signaling, growth and metabolic processes. To establish a molecular basis for MYC support of KRAS-ERK-driven PDAC growth, we determined the gene transcription changes caused by acute loss of MYC function and identified 1,685 MYC-dependent (UP) and 1,325 MYC-inhibited (DN) genes. Dependency Map analyses demonstrated that MYC UP but not DN genes are essential for PDAC growth. Instead, pathway analyses support MYC DN genes as a secondary RHO GTPase-mediated compensatory response to oncogenic stress. We found that 36% of ERK-dependent genes are MYC-dependent, supporting the dominant role of MYC in driving ERK-regulated gene expression. Finally, proteomic profiling revealed that MYC regulated a complex kinome comprised of protein kinases that likely contribute to MYC-driven cancer growth. We conclude that MYC supports KRAS-ERK-dependent PDAC growth through regulation of a complex transcriptome and kinome.
2026-01-15 | PXD061413 | Pride
Project description:RNA-Seq Analysis of c-MYC inducible knockdown in Human breast Cancer cells
| PRJNA738897 | ENA
Project description:The MYC transcription factor is a key regulator of growth during development and a potent cancer driver when its expression is dysregulated. Strategies to inhibit MYC oncogenic activity would mark a significant advance, but decades of efforts to target MYC directly have not been fruitful. Understanding how MYC drives transformation and tumor growth may provide new therapeutic avenues in a variety of cancers. By intersecting two independent genome-wide screens, we identified loss of the chromatin remodeler Chromodomain-Helicase DNA-binding 1 (CHD1) as a potential synthetic lethal target in MYC-driven breast cancer. Knockdown of CHD1 in a xenograft model of MYC-driven breast cancer suppresses tumor growth in vivo. In tissue culture models, we found that knockdown of CHD1 suppresses cell proliferation and induces cell death, specifically when MYC is overexpressed. Mechanistically, we found that CHD1 is required to maintain an open chromatin landscape and a transcriptional program associated with cancer progression in MYC overexpressing breast cells. Follow-up experiments indicate that this synthetic lethality may arise from nucleolar stress and p53 activation. These findings provide new insights on the chromatin-level regulation of MYC-driven breast cancer and uncover CHD1 as a novel synthetic vulnerability and potential therapeutic target.
2026-02-26 | GSE303747 | GEO
Project description:Targeting the PI3K-AKT-mTOR pathway is a promising therapeutic strategy for breast cancer treatment. However, low response rates and the development of acquired resistance to PI3K-AKT-mTOR inhibitors remain major challenges for successful patient treatment. Here, we show that MYC activation is a central and clinically relevant mechanism of resistance to mTOR inhibitors (mTORi) in breast cancer. Multi-omic profiling of mouse invasive lobular carcinoma (ILC) tumors revealed recurrent focal Myc amplification in tumors that acquire resistance to the mTORi AZD8055. The gained MYC activity was significantly associated with biological processes linked to mTORi response. Specifically, MYC counteracted the translation inhibitory effect induced by mTORi by promoting the translation of ribosomal proteins. In vitro and in vivo induction of MYC conferred resistance to AZD8055 as well as the clinically approved mTORi everolimus, both in mouse models of ILC and human breast cancer models. Conversely, AZD8055-resistant ILC cells depended on MYC, as demonstrated by synergistic growth inhibition using mTORi and MYCi combination treatment. Notably, MYC status was significantly associated with poor response to everolimus therapy in metastatic breast cancer patients. Thus, MYC is a clinically relevant determinant of mTORi resistance that may guide the selection of breast cancer patients for mTOR targeted therapies.
2023-05-02 | PXD041927 | Pride
Project description:The MYC transcription factor is a key regulator of growth during development and a potent cancer driver when its expression is dysregulated. Strategies to inhibit MYC oncogenic activity would mark a significant advance, but decades of efforts to target MYC directly have not been fruitful. Understanding how MYC drives transformation and tumor growth may provide new therapeutic avenues in a variety of cancers. By intersecting two independent genome-wide screens, we identified loss of the chromatin remodeler Chromodomain-Helicase DNA-binding 1 (CHD1) as a potential synthetic lethal target in MYC-driven breast cancer. Knockdown of CHD1 in a xenograft model of MYC-driven breast cancer suppresses tumor growth in vivo. In tissue culture models, we found that knockdown of CHD1 suppresses cell proliferation and induces cell death, specifically when MYC is overexpressed. Mechanistically, we found that CHD1 is required to maintain an open chromatin landscape and a transcriptional program associated with cancer progression in MYC overexpressing breast cells. Follow-up experiments indicate that this synthetic lethality may arise from nucleolar stress and p53 activation. These findings provide new insights on the chromatin-level regulation of MYC-driven breast cancer and uncover CHD1 as a novel synthetic vulnerability and potential therapeutic target.
2026-02-26 | GSE303748 | GEO
Project description:Hepatoblastoma (HB) is associated with aberrant activation of the b-catenin and Hippo/YAP signaling pathways. Over-expression of mutant b-catenin and YAP in mice induces HBs that express high levels of c-Myc (Myc). In light of recent observations that Myc in unnecessary for long-term hepatocyte proliferation, we have now examined its role in HB pathogenesis using the above model. While Myc was found to be dispensable for in vivo HB initiation it was necessary to sustain rapid tumor growth. Gene expression profiling identified key molecular differences between myc+/+ (WT) and myc-/- (KO) hepatocytes and HBs that explain these behaviors. In HBs, these included both Myc-dependent and Myc-independent increases in families of transcripts encoding ribosomal proteins, non-structural factors affecting ribosome assembly and function and enzymes catalyzing glycolysis, lipid bio-synthesis and fatty acid b-oxidation. Myc-independent metabolic changes associated with HBs included dramatic reductions in mitochondrial mass and oxidative function and increases in ATP content and pyruvate dehydrogenase activity. Myc-dependent metabolic changes included higher levels of neutral lipid and acetyl-CoA in WT tumors. The latter correlated with higher histone H3 acetylation. Collectively, our results indicate that Myc’s role in HB pathogenesis is to impose mutually dependent changes in gene expression and metabolic re-programming that are unattainable in non-transformed cells and that cooperate to maximize tumor growth.
2016-10-28 | GSE87578 | GEO
Project description:Purpose: discover the downstream pathways and the mechanism of target activation by the p53:Myc axis in normal mammary and cancer stem cells Methods: we performed ChIPseq experiments from NMuMG cells grown in adhesion under standard conditions Results: the p53:Myc axis orchestrates its transcriptional response in mammary-epithelial cells via a dual and overlapping mechanism: i) a tightly controlled epistasis driven by p53 and executed by Myc, and ii) a co-operative double occupancy of their downstream effectors at different regulatory regions
2019-01-21 | GSE87002 | GEO
Project description:Hitherto, most studies on POLD1 have mainly focused on the effect of POLD1 inactivation mutation in tumors. Nonetheless, the mechanism underlying high POLD1 expression in tumorigenesis remains elusive. Herein, we substantiated the pro-carcinogenic role of POLD1 in bladder cancer (BLCA) and found that POLD1 expression is related to malignancy and prognosis of BLCA. Next, we demonstrated that POLD1 could promote proliferation and metastasis of BLCA via MYC. Mechanistically, we demonstrated that POLD1 was able to stabilize MYC in a manner independent of DNA polymerase activity. POLD1 attenuated the FBXW7-mediated ubiquitination degradation of MYC by directly binding to the MYC homology box 1 domain competitively with FBXW7. Moreover, we found that POLD1 can form a complex with MYC to promote the transcriptional activity of MYC. MYC could also transcriptionally activate POLD1, forming a POLD1-MYC positive feedback loop to enhance the pro-carcinogenic effect of POLD1-MYC on BLCA. Overall, our study suggests a novel MYC-driven mechanism for BLCA, and POLD1 has the potential as a biomarker for BLCA.
2023-03-29 | PXD040806 | Pride
Project description:It has been estimated that about 11% of cellular genes present a functional E box to which MYC can associate on the genome. MYC silencing demonstrated that MYC recruits PIM1 at specific MYC binding sites and confocal microscopy following growth factor treatment, showed an elevated degree of nuclear co-localization of PIM1 with nascent transcripts and with MYC suggesting that PIM1 is recruited by MYC to a large number of sites. To understand the actual extension of PIM1 and MYC co-operation in gene transcription we performed expression profile analysis of 293 cells silenced either for MYC or PIM1 at 120 minutes after serum treatment. MYC silencing affected the expression of 1026 genes of which 818 were up-regulated and 208 were down-regulated. Comparison of genes regulated by MYC with those regulated by PIM1, by RNAi silencing, showed that PIM1 contributes to the regulation of 207 genes out of the 1026 MYC-regulated genes. Thus, a subset of 20% of MYC-regulated genes, are also regulated by PIM1. The co-regulated includes genes involved in cell metabolism, protein synthesis, cycle progression, and oncogenesis. Interestingly, a large number of genes are transcriptional factors, which suggests that PIM1 participates in MYC-dependent regulatory networks. Experiment Overall Design: The gene expression analysis was performed by hybridizing RNA samples to the Whole Human Genome Oligo Microarray from Agilent Technologies. Samples were obtained from 293 cells, treated with serum for 120 minutes, expressing either two independent MYC shRNA (shMYC#1 and shMYC#2) or their relative scrambled shRNA (shsM#1 and shsM#2) for MYC expression analysis; two independent PIM1 shRNA (shPIM1#1 and shPIM1#2) or their relative scrambled shRNA (shsP#1 and shsP#2) for PIM1 expression analysis.
2008-06-15 | E-GEOD-7960 | biostudies-arrayexpress