A5059618857- Ovarian cancer diagnosis and treatment
- Estrogen and related hormone effects
- Chromatin Remodeling and Cancer
- Peptidase Inhibition and Analysis
- Cancer-related Molecular Pathways
- Ubiquitin and proteasome pathways
- Cancer Mechanisms and Therapy
- Signaling Pathways in Disease
- Renal cell carcinoma treatment
- S100 Proteins and Annexins
- Protein Degradation and Inhibitors
- PI3K/AKT/mTOR signaling in cancer
- Genomics and Chromatin Dynamics
- DNA Repair Mechanisms
- Cardiac Fibrosis and Remodeling
- Cancer-related gene regulation
- Retinoids in leukemia and cellular processes
- Virus-based gene therapy research
- Epigenetics and DNA Methylation
- RNA regulation and disease
- Advanced Breast Cancer Therapies
- Wnt/β-catenin signaling in development and cancer
- Cytokine Signaling Pathways and Interactions
- PARP inhibition in cancer therapy
- Computational Drug Discovery Methods
The Netherlands Cancer Institute
2000-2022
Oncode Institute
2018-2022
Cancer Genomics Centre
2014
Hubrecht Institute for Developmental Biology and Stem Cell Research
2005
The estrogen receptor (ER) is an important regulator of growth and differentiation breast epithelium. Transactivation by ER depends on a leucine-rich motif, which constitutes ligand-regulated binding site for steroid coactivators (SRCs). Cyclin D1 frequently amplified in cancer can activate through direct binding. We show here that cyclin also interacts ligand-independent fashion with the SRC-1 family motif resembles coactivator nuclear receptors. By acting as bridging factor between SRCs,...
E2F DNA binding sites are found in a number of genes whose expression is tightly regulated during the cell cycle. The activity transcription factors by association with specific repressor molecules that can bind and inhibit transactivation domain. For E2F-1, E2F-2, E2F-3, product retinoblastoma gene, pRb. E2f-4 interacts pRb-related p107 not pRb itself. Recently, cDNA encoding third member gene family, p130, was isolated. p130 also activity, primarily G0 phase We report here cloning fifth...
Current treatment for advanced stage ovarian clear cell cancer is severely hampered by a lack of effective systemic therapy options, leading to poor outlook these patients. Sequencing studies revealed that ARID1A mutated in over 50% carcinomas. To search rational approach target cancers with mutations, we performed kinome-centered lethality screens large panel carcinoma lines. Using the largest OCCC line established date, show here BRD2 inhibition predominantly lethal cells. Importantly,...
Despite the substantial progress in development of targeted anticancer drugs, treatment failure due to primary or acquired resistance is still a major hurdle effective most advanced human cancers. Understanding these mechanisms will be instrumental improve personalized cancer treatment.Genome-wide loss-of-function genetic screens were performed identify genes implicated HER2/PI3K/mTOR targeting agents HER2+ breast cell lines. Expression and adjuvant trastuzumab response data from trials...
The Wnt signaling cascade is a central regulator of cell fate determination during embryonic development, whose deregulation contributes to oncogenesis. Naked cuticle the first Wnt-induced antagonist found in this pathway, establishing negative-feedback loop that limits signal required for early segmentation. In addition, proposed function as switch, acting restrict classical and activate second pathway controls planar polarity gastrulation movements vertebrates. Little known about...
Abstract Purpose: Advanced-stage ovarian clear cell carcinoma (OCCC) is unresponsive to conventional platinum-based chemotherapy. Frequent alterations in OCCC include deleterious mutations the tumor suppressor ARID1A and activating PI3K subunit PIK3CA. In this study, we aimed identify currently unknown mutated kinases patients with test druggability of downstream affected pathways models. Experimental Design: a large set (n = 124), human kinome (518 kinases) additional cancer-related genes...
Adenovirus E1A encodes two nuclear phosphoproteins that can transform primary rodent fibroblasts in culture. Transformation by is mediated at least part through binding to several cellular proteins, including the three members of retinoblastoma family growth inhibitory proteins. We report here cloning a novel murine cDNA whose encoded protein interacts with both adenovirus type 5 and 12 The E1A-interacting shares significant sequence homology ubiquitin-conjugating enzymes, related proteins...
Abstract Tamoxifen is one of the most widely used endocrine agents for treatment estrogen receptor α (ERα)–positive breast cancer. Although effective in patients, resistance to tamoxifen a clinically significant problem and mechanisms responsible remain elusive. To address this problem, we performed large scale loss-of-function genetic screen ZR-75-1 luminal cancer cells identify candidate genes. In manner, found that loss function deubiquitinase USP9X prevented proliferation arrest by...
The c-myc gene encodes a sequence-specific DNA binding protein that activates transcription of cellular genes. Transcription activation by Myc proteins is regulated phosphorylation serine and threonine residues within the transactivation domain complex formation with retinoblastoma-related p107. In Burkitt's lymphoma, missense mutations c-Myc have been found high frequency. It has reported mutant derived from lymphoma cell lines are resistant to inhibition p107, thus providing rationale for...
The helix-loop-helix transcription factor TFE3 has been suggested to play a role in the control of cell growth by acting as binding partner transcriptional regulators such E2F3, SMAD3, and LEF-1. Furthermore, translocations/TFE3 fusions have directly implicated tumorigenesis. Surprisingly, however, direct functional for regulation proliferation not reported. By screening retroviral cDNA expression libraries identify cDNAs that confer resistance pRB-induced arrest, we found overrides arrest...
Low-grade serous ovarian cancer (LGSOC) is a rare subtype of epithelial with high fatality rates in advanced stages due to its chemoresistant properties. LGSOC characterized by activation MAPK signaling, and recent clinical trials indicate that the MEK inhibitor (MEKi) trametinib may be good treatment option for subset patients. Understanding MEKi-resistance mechanisms subsequent identification rational drug combinations suppress resistance greatly improve strategies. Both gain-of-function...
The discovery of a cellular response against doublestranded RNA (Fire et al. 1998) has provided one themost powerful tools to manipulate gene expression andthis revolutionized loss-of-function genetics inCaenorhabditis elegans and Drosophila (Ashrafi al.2003; Kamath 2003; Lum 2003). In mostmammalian cells, however, the introduction long double-stranded provokes an interferon response, leading general shutoff protein synthesis (Stark al.1998). This can be bypassed by using chemically...
Abstract Introduction: Current treatment for advanced stage ovarian clear cell cancer is severely hampered by a lack of effective systemic therapy options, leading to poor outlook these patients. Given that ARID1A inactivated mutation in over 50% carcinomas, we pursued an synthetic lethal screening strategy identify druggable targets OCCC. Experimental procedures: We performed kinome short hairpin (shRNA) screens large panel (n=14) OCCC lines having different status. Hit validation was with...
<div>Abstract<p>Tamoxifen is one of the most widely used endocrine agents for treatment estrogen receptor α (ERα)–positive breast cancer. Although effective in patients, resistance to tamoxifen a clinically significant problem and mechanisms responsible remain elusive. To address this problem, we performed large scale loss-of-function genetic screen ZR-75-1 luminal cancer cells identify candidate genes. In manner, found that loss function deubiquitinase USP9X prevented...
<p>Figure S2. QPCR validation of ChIP-seq data at 45 minutes ligand treatment. (A) Genome browser snapshots ERα chromatin binding events the RARA and NRIP1 loci. Cells were treated for 48 hours, prior to fixation. shGFP (blue) shUSP9X (red) conditions tested. Tag count genomic coordinates are shown. (B) ChIP-QPCR locations, indicated in A. during (white) (black) Enrichment over negative control region was assessed. Error bar shows SD values from triplicate measurements.</p>