A5082253864- Estrogen and related hormone effects
- HER2/EGFR in Cancer Research
- Epigenetics and DNA Methylation
- Genomics and Chromatin Dynamics
- Bioinformatics and Genomic Networks
- Cancer-related gene regulation
- RNA modifications and cancer
- Cancer Cells and Metastasis
- Cancer, Hypoxia, and Metabolism
- Cancer, Lipids, and Metabolism
- Gene expression and cancer classification
- Wnt/β-catenin signaling in development and cancer
- Prostate Cancer Treatment and Research
- Cytokine Signaling Pathways and Interactions
- Nutrition, Genetics, and Disease
- Metabolism, Diabetes, and Cancer
- Protein Tyrosine Phosphatases
- PI3K/AKT/mTOR signaling in cancer
- Cancer-related Molecular Pathways
- Cancer Genomics and Diagnostics
- RNA Research and Splicing
- Mechanisms of cancer metastasis
- Histone Deacetylase Inhibitors Research
- CRISPR and Genetic Engineering
- Protein Degradation and Inhibitors
Institute for Research in Immunology and Cancer
2020-2024
Université de Montréal
2012-2024
Princess Margaret Cancer Centre
2016-2023
University Health Network
2016-2023
McGill University
2006-2023
Duke University
2022
University of Toronto
2016-2019
McGill University Health Centre
2005-2014
Saint John's Health Center
2013
Cold Spring Harbor Laboratory
2012-2013
Nuclear receptors can activate diverse biological pathways within a target cell in response to their cognate ligands, but how this compartmentalization is achieved at the level of gene regulation poorly understood. We used genome-wide analysis promoter occupancy by estrogen receptor α (ERα) MCF-7 cells investigate molecular mechanisms underlying action 17β-estradiol (E 2 ) controlling growth breast cancer cells. identified 153 promoters bound ERα presence E . Motif-finding algorithms...
Abstract Triple negative breast cancer (TNBC) is a deadly form of due to the development resistance chemotherapy affecting over 30% patients. New therapeutics and companion biomarkers are urgently needed. Recognizing elevated expression glucose transporter 1 (GLUT1, encoded by SLC2A1 ) associated metabolic dependencies in TNBC, we investigated vulnerability TNBC cell lines patient-derived samples GLUT1 inhibition. We report that genetic or pharmacological inhibition with BAY-876 impairs...
Abstract Triple-negative breast cancer (TNBC) is the most aggressive subtype with worst prognosis and few effective therapies. Here we identified MS023, an inhibitor of type I protein arginine methyltransferases (PRMTs), which has antitumor growth activity in TNBC. Pathway analysis TNBC cell lines indicates that activation interferon responses before after MS023 treatment a functional biomarker determinant response, these observations extend to panel human-derived organoids. Inhibition PRMT...
The identification of regulatory regions is one the most important and challenging problems toward functional annotation human genome. In higher eukaryotes, transcription-factor (TF) binding sites are often organized in clusters called cis-regulatory modules (CRM). While prediction individual TF-binding a notoriously difficult problem, CRM has proven to be somewhat more reliable. Starting from set predicted for than 200 TF families documented Transfac, we describe an algorithm relying on...
Posttranslational modifications are instrumental to achieve gene- and tissue-specific regulatory outcomes by transcription factors. Nuclear receptors dynamically modulated several types of posttranslational including phosphorylation, methylation, acetylation, ubiquitination, sumoylation. The estrogen-related receptor alpha (ERRalpha, NR3B1) is phosphorylated on multiple sites, sumoylated in the amino-terminal region a phosphorylation-dependent manner. Here we demonstrate that ERRalpha...
Estrogen-related receptor alpha (ERRalpha) is an orphan nuclear receptor, the expression of which correlates with negative prognosis in breast cancer. ERRalpha shares functional features estrogen (ERalpha) and its activity modulated by ERBB2 signaling pathway. Using genome-wide binding sites location analyses ERalpha-positive ERalpha-negative cancer cell lines, we show that ERalpha display strict site specificity maintain independent mechanisms transcriptional activation. Nonetheless,...
Abstract Background Glutamine metabolism is a central metabolic pathway in cancer. Recently, reductive carboxylation of glutamine for lipogenesis has been shown to constitute key anabolic route cancer cells. However, little known regarding regulators the various pathways Methods The impact PGC-1α and ERRα on enzyme expression was assessed ERBB2+ breast cell lines with quantitative RT-PCR, chromatin immunoprecipitation, immunoblotting experiments. flux quantified using 13 C-labeled GC/MS...
Bromodomains (BRDs) are conserved protein interaction modules which recognize (read) acetyl-lysine modifications, however their role(s) in regulating cellular states and potential as targets for the development of targeted treatment strategies is poorly understood. Here we present a set 25 chemical probes, selective small molecule inhibitors, covering 29 human bromodomain targets. We comprehensively evaluate selectivity this probe-set using BROMOscan demonstrate utility identifying roles...
Tumor progression upon treatment arises from preexisting resistant cancer cells and/or adaptation of persister committing to an expansion phase. Here, we show that evasion viral mimicry response allows the growth taxane-resistant triple-negative breast (TNBC). This is enabled by epigenetic state adapted taxane-induced metabolic stress, where DNA hypomethylation over loci enriched in transposable elements (TE) compensated large chromatin domains H3K27me3 warrant TE repression. creates a...
Despite the initial benefits of treating HER2-amplified breast cancer patients with tyrosine kinase inhibitor lapatinib, resistance inevitably develops. Here we report that lapatinib induces degradation nuclear receptor ERRα, a master regulator cellular metabolism, and expression ERRα is restored in lapatinib-resistant cells through reactivation mTOR signalling. Re-expression resistant triggers metabolic adaptations favouring mitochondrial energy metabolism increased glutamine as well ROS...
The androgen receptor (AR) signaling axis plays a key role in the pathogenesis of prostate cancer. In this study, we found that protein tyrosine phosphatase PTP1B, well-established regulator metabolic signaling, was induced after stimulation AR-expressing cancer cells. PTP1B induction by occurred at mRNA and levels to increase activity. High-resolution chromosome mapping revealed AR recruitment two response elements within first intron encoding gene PTPN1, correlating with an AR-mediated RNA...
Although ERBB2 amplification and overexpression is correlated with poor outcome in breast cancer, the molecular mechanisms underlying aggressive nature of these tumors has not been fully elucidated. To investigate this further, we have used a transgenic mouse model ErbB2-driven tumor progression (ErbB2(KI) model) that recapitulates clinically relevant events, including selective core erbB2 amplicon. By comparing transcriptional profiles ErbB2(KI) mammary human ERBB2-positive cancers, show...
Abstract Predicting and treating recurrence in intermediate-risk prostate cancer patients remains a challenge despite having identified genomic instability [1] hypoxia [2, 3] as risk factors. This underlies challenges assigning the functional impact of these factors to mechanisms promoting progression. Here we show chronic (CH), observed tumours [4], leads adoption an androgen-independent state cells. Specifically, CH results cells adopting transcriptional metabolic alterations typical...
The estrogen-related receptor α (ERRα) is an orphan member of the superfamily nuclear receptors involved in control energy metabolism. In particular, ERRα induces a high expenditure presence coactivator PGC-1α. However, knockout mice have reduced fat mass and are resistant to diet-induced obesity. expressed epithelial cells small intestine, because intestine first step chain, we investigated whether plays function dietary handling. Gene expression profiling identified subset genes oxidative...
Overexpression of ERBB2 and its neighboring genes on chromosome 17 occurs in approximately 25% breast tumors is associated with poor prognosis. While amplification the 17q12-21 chromosomal region often correlates an increase transcriptional rates locus, molecular mechanisms factors involved coordinated expression residing within amplicon remain largely unknown. Here we demonstrate that estrogen-related receptor α (ERRα, NR3B1) coregulator PGC-1β are key effectors this process. Using a mouse...
The mammary epithelium depends on specific lineages and their stem progenitor function to accommodate hormone-triggered physiological demands in the adult female. Perturbations of these underpin breast cancer risk, yet our understanding normal cell composition is incomplete. Here, we build a multimodal resource for gland through comprehensive profiling primary epigenomes, transcriptomes, proteomes. We define systems-level relationships between chromatin–DNA–RNA–protein states, identify...
The identification of estrogen receptor (ERalpha) target genes is crucial to our understanding its predominant role in breast cancer. In this study, we used a chromatin immunoprecipitation (ChIP)-cloning strategy identify ERalpha-regulatory modules and associated the human cancer cell line MCF-7. We isolated 12 transcriptionally active genomic that recruit ERalpha coactivator steroid (SRC)-3 different intensities vivo. One identified located 3.7 kb downstream first transcriptional start site...
Highlights•The transcriptional repressor PCGF6 negatively regulates dendritic cell activation•PCGF6 H3K4me3 levels at genes important for function•PCGF6 interacts with the histone demethylase JARID1cSummaryPro-inflammatory signals provided by microenvironment are critical to activate cells (DCs), components of innate immune system that shape both and adaptive immunity. However, prevent inappropriate activation, mechanisms must be in place restrain DC activation ensure DCs activated only once...