151 results found
Ali S, Periyasamy M, Patel H, et al., 2015, APOBEC3B mediated cytidine deamination is required for estrogen receptor action in breast cancer, Cell Reports, Vol: 13, Pages: 108-121, ISSN: 2211-1247
Estrogen receptor α (ERα) is the key transcriptional driver in a large proportion of breast cancers. We report that APOBEC3B (A3B) is required for regulation of gene expression by ER and acts by causing C-to-U deamination at ER binding regions. We show that these C-to-U changes lead to the generation of DNA strand breaks through activation of base excision repair (BER) and to repair by non-homologous end-joining (NHEJ) pathways. We provide evidence that transient cytidine deamination by A3B aids chromatin modification and remodelling at the regulatory regions of ER target genes that promotes their expression. A3B expression is associated with poor patient survival in ER+ breast cancer, reinforcing the physiological significance of A3B for ER action.
Kramer H, Lai C, Dattani H, et al., 2015, LRH-1 drives colon cancer cell growth by repressing the expression of the CDKN1A gene in a p53-dependent manner, Nucleic Acids Research, Vol: 44, Pages: 582-594, ISSN: 1362-4962
Liver receptor homologue 1 (LRH-1) is an orphan nuclearreceptor that has been implicated in the progressionof breast, pancreatic and colorectal cancer(CRC). To determine mechanisms underlying growthpromotion by LRH-1 in CRC, we undertook global expressionprofiling following siRNA-mediated LRH-1knockdown in HCT116 cells, which require LRH-1 forgrowth and in HT29 cells, in which LRH-1 does notregulate growth. Interestingly, expression of the cellcycle inhibitor p21 (CDKN1A) was regulated by LRH-1 in HCT116 cells. p21 regulation was not observedin HT29 cells, where p53 is mutated. p53 dependencefor the regulation of p21 by LRH-1 was confirmed byp53 knockdown with siRNA, while LRH-1-regulationof p21 was not evident in HCT116 cells where p53 hadbeen deleted. We demonstrate that LRH-1-mediatedp21 regulation in HCT116 cells does not involve alteredp53 protein or phosphorylation, and we showthat LRH-1 inhibits p53 recruitment to the p21 promoter,likely through a mechanism involving chromatinremodelling. Our study suggests an importantrole for LRH-1 in the growth of CRC cells that retainwild-type p53.
Lin M-L, Patel H, Remenyi J, et al., 2015, Expression profiling of nuclear receptors in breast cancer identifies TLX as a mediator of growth and invasion in triple-negative breast cancer, Oncotarget, Vol: 6, Pages: 21685-21703, ISSN: 1949-2553
he Nuclear Receptor (NR) superfamily of transcription factors comprises 48 members, several of which have been implicated in breast cancer. Most important is estrogen receptor-α (ERα), which is a key therapeutic target. ERα action is facilitated by co-operativity with other NR and there is evidence that ERα function may be recapitulated by other NRs in ERα-negative breast cancer. In order to examine the inter-relationships between nuclear receptors, and to obtain evidence for previously unsuspected roles for any NRs, we undertook quantitative RT-PCR and bioinformatics analysis to examine their expression in breast cancer. While most NRs were expressed, bioinformatic analyses differentiated tumours into distinct prognostic groups that were validated by analyzing public microarray data sets. Although ERα and progesterone receptor were dominant in distinguishing prognostic groups, other NR strengthened these groups. Clustering analysis identified several family members with potential importance in breast cancer. Specifically, RORγ is identified as being co-expressed with ERα, whilst several NRs are preferentially expressed in ERα-negative disease, with TLX expression being prognostic in this subtype. Functional studies demonstrated the importance of TLX in regulating growth and invasion in ERα-negative breast cancer cells.
Guttery DS, Page K, Hills A, et al., 2015, Noninvasive Detection of Activating Estrogen Receptor 1 (ESR1) Mutations in Estrogen Receptor-Positive Metastatic Breast Cancer, Clinical Chemistry, Vol: 61, Pages: 974-982, ISSN: 1530-8561
BACKGROUND: Activating mutations in the estrogen receptor 1 (ESR1) gene are acquired on treatment and can drive resistance to endocrine therapy. Because of the spatial and temporal limitations of needle core biopsies, our goal was to develop a highly sensitive, less invasive method of detecting activating ESR1 mutations via circulating cell-free DNA (cfDNA) and tumor cells as a “liquid biopsy.”METHODS: We developed a targeted 23-amplicon next-generation sequencing (NGS) panel for detection of hot-spot mutations in ESR1, phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA), tumor protein p53 (TP53), fibroblast growth factor receptor 1 (FGFR1), and fibroblast growth factor receptor 2 (FGFR2) in 48 patients with estrogen receptor-α–positive metastatic breast cancer who were receiving systemic therapy. Selected mutations were validated using droplet digital PCR (ddPCR).RESULTS: Nine baseline cfDNA samples had an ESR1 mutation. NGS detected 3 activating mutations in ESR1, and 3 hot-spot mutations in PIK3CA, and 3 in TP53 in baseline cfDNA, and the ESR1 p.D538G mutation in 1 matched circulating tumor cell sample. ddPCR analysis was more sensitive than NGS and identified 6 additional baseline cfDNA samples with the ESR1 p.D538G mutation at a frequency of <1%. In serial blood samples from 11 patients, 4 showed changes in cfDNA, 2 with emergence of a mutation in ESR1. We also detected a low frequency ESR1 mutation (1.3%) in cfDNA of 1 primary patient who was thought to have metastatic disease but was clear by scans.CONCLUSIONS: Early identification of ESR1 mutations by liquid biopsy might allow for cessation of ineffective endocrine therapies and switching to other treatments, without the need for tissue biopsy and before the emergence of metastatic disease.
Abduljabbar R, Negm OH, Lai C-F, et al., 2015, Clinical and biological significance of glucocorticoid receptor (GR) expression in breast cancer, BREAST CANCER RESEARCH AND TREATMENT, Vol: 150, Pages: 335-346, ISSN: 0167-6806
Abduljabbar R, Al-Kaabi MM, Negm OH, et al., 2015, Prognostic and biological significance of peroxisome proliferator-activated receptor-gamma in luminal breast cancer, BREAST CANCER RESEARCH AND TREATMENT, Vol: 150, Pages: 511-522, ISSN: 0167-6806
Rudraraju B, Droog M, Abdel-Fatah TMA, et al., 2014, Phosphorylation of activating transcription factor-2 (ATF-2) within the activation domain is a key determinant of sensitivity to tamoxifen in breast cancer, BREAST CANCER RESEARCH AND TREATMENT, Vol: 147, Pages: 295-309, ISSN: 0167-6806
Xu Y, Zhang H, Lit LC, et al., 2014, The Kinase LMTK3 Promotes Invasion in Breast Cancer Through GRB2-Mediated Induction of Integrin beta(1), SCIENCE SIGNALING, Vol: 7, ISSN: 1945-0877
Brooke GN, Powell SM, Lavery DN, et al., 2014, Engineered repressors are potent inhibitors of androgen receptor activity, Oncotarget, Vol: 5, Pages: 959-969, ISSN: 1949-2553
Prostate cancer growth is dependent upon the Androgen Receptor (AR) pathway, hence therapies for this disease often target this signalling axis. Such therapies are successful in the majority of patients but invariably fail after a median of 2 years and tumours progress to a castrate resistant stage (CRPC). Much evidence exists to suggest that the AR remains key to CRPC growth and hence remains a valid therapeutic target. Here we describe a novel method to inhibit AR activity, consisting of an interaction motif, that binds to the AR ligand-binding domain, fused to repression domains. These ‘engineered repressors’ are potent inhibitors of AR activity and prostate cancer cell growth and importantly inhibit the AR under circumstances in which conventional therapies would be predicted to fail, such as AR mutation and altered cofactor levels.
Ottaviani S, Brooke GN, O'Hanlon-Brown C, et al., 2013, Characterisation of the androgen regulation of glycine N-methyltransferase in prostate cancer cells, JOURNAL OF MOLECULAR ENDOCRINOLOGY, Vol: 51, Pages: 301-312, ISSN: 0952-5041
Lai C-F, Flach KD, Alexi X, et al., 2013, Co-regulated gene expression by oestrogen receptor alpha and liver receptor homolog-1 is a feature of the oestrogen response in breast cancer cells, NUCLEIC ACIDS RESEARCH, Vol: 41, Pages: 10228-10240, ISSN: 0305-1048
Eccles SA, Aboagye EO, Ali S, et al., 2013, Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer, Breast Cancer Research, Vol: 15, Pages: R-R, ISSN: 1465-542X
IntroductionBreast cancer remains a significant scientific, clinical and societal challenge. This gap analysis has reviewed and critically assessed enduring issues and new challenges emerging from recent research, and proposes strategies for translating solutions into practice.MethodsMore than 100 internationally recognised specialist breast cancer scientists, clinicians and healthcare professionals collaborated to address nine thematic areas: genetics, epigenetics and epidemiology; molecular pathology and cell biology; hormonal influences and endocrine therapy; imaging, detection and screening; current/novel therapies and biomarkers; drug resistance; metastasis, angiogenesis, circulating tumour cells, cancer ‘stem’ cells; risk and prevention; living with and managing breast cancer and its treatment. The groups developed summary papers through an iterative process which, following further appraisal from experts and patients, were melded into this summary account.ResultsThe 10 major gaps identified were: (1) understanding the functions and contextual interactions of genetic and epigenetic changes in normal breast development and during malignant transformation; (2) how to implement sustainable lifestyle changes (diet, exercise and weight) and chemopreventive strategies; (3) the need for tailored screening approaches including clinically actionable tests; (4) enhancing knowledge of molecular drivers behind breast cancer subtypes, progression and metastasis; (5) understanding the molecular mechanisms of tumour heterogeneity, dormancy, de novo or acquired resistance and how to target key nodes in these dynamic processes; (6) developing validated markers for chemosensitivity and radiosensitivity; (7) understanding the optimal duration, sequencing and rational combinations of treatment for improved personalised therapy; (8) validating multimodality imaging biomarkers for minimally invasive diagnosis and monitoring of responses in primary and metastatic disease
Kaliszczak M, Patel H, Kroll SHB, et al., 2013, Development of a cyclin-dependent kinase inhibitor devoid of ABC transporter-dependent drug resistance, British Journal of Cancer, Vol: 109, Pages: 2356-2367, ISSN: 1532-1827
background: Cyclin-dependent kinases (CDKs) control cell cycle progression, RNA transcription and apoptosis, making them attractive targets for anticancer drug development. Unfortunately, CDK inhibitors developed to date have demonstrated variable efficacy.methods: We generated drug-resistant cells by continuous low-dose exposure to a model pyrazolo[1,5-a]pyrimidine CDK inhibitor and investigated potential structural alterations for optimal efficacy.results: We identified induction of the ATP-binding cassette (ABC) transporters, ABCB1 and ABCG2, in resistant cells. Assessment of features involved in the ABC transporter substrate specificity from a compound library revealed high polar surface area (>100 Å2) as a key determinant of transporter interaction. We developed ICEC-0782 that preferentially inhibited CDK2, CDK7 and CDK9 in the nanomolar range. The compound inhibited phosphorylation of CDK substrates and downregulated the short-lived proteins, Mcl-1 and cyclin D1. ICEC-0782 induced G2/M arrest and apoptosis. The permeability and cytotoxicity of ICEC-0782 were unaffected by ABC transporter expression. Following daily oral dosing, the compound inhibited growth of human colon HCT-116 and human breast MCF7 tumour xenografts in vivo by 84% and 94%, respectively.conclusion: We identified a promising pyrazolo[1,5-a]pyrimidine compound devoid of ABC transporter interaction, highly suitable for further preclinical and clinical evaluation for the treatment of cancer.
Faronato M, Lombardo Y, Filipovic A, et al., 2013, Anti-Nicastrin antibodies for the treatment of endocrine resistant breast cancer., 104th Annual Meeting of the American-Association-for-Cancer-Research (AACR), Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Long J, Delahanty RJ, Li G, et al., 2013, A Common Deletion in the APOBEC3 Genes and Breast Cancer Risk, JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE, Vol: 105, Pages: 573-579, ISSN: 0027-8874
Rey J, Hu H, Kyle F, et al., 2012, Discovery of a New Class of Liver Receptor Homolog-1 (LRH-1) Antagonists: Virtual Screening, Synthesis and Biological Evaluation, CHEMMEDCHEM, Vol: 7, Pages: 1909-1914, ISSN: 1860-7179
Lake MC, Quang-De N, Ali S, et al., 2012, Development of a Novel Molecular Sensor for Imaging Estrogen Receptor-Coactivator Protein-Protein Interactions, PLOS ONE, Vol: 7, ISSN: 1932-6203
Ottaviani S, Brown CO, Waxman J, et al., 2012, Identification of glycine N-methyltransferase-regulated genes in prostate cancer cells, CANCER RESEARCH, Vol: 72, ISSN: 0008-5472
Ross-Innes CS, Stark R, Teschendorff AE, et al., 2012, Differential oestrogen receptor binding is associated with clinical outcome in breast cancer, NATURE, Vol: 481, Pages: 389-U177, ISSN: 0028-0836
Ross-Innes CS, Stark AR, Teschendorff AE, et al., 2012, Differential oestrogen receptor binding is associated with clinical outcome in breast cancer, Nature, Vol: 481, Pages: 389-391
Oestrogen receptor-α (ER) is the defining and driving transcription factor in the majority of breast cancers and its target genes dictate cell growth and endocrine response, yet genomic understanding of ER function has been restricted to model systems1, 2, 3. Here we map genome-wide ER-binding events, by chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq), in primary breast cancers from patients with different clinical outcomes and in distant ER-positive metastases. We find that drug-resistant cancers still recruit ER to the chromatin, but that ER binding is a dynamic process, with the acquisition of unique ER-binding regions in tumours from patients that are likely to relapse. The acquired ER regulatory regions associated with poor clinical outcome observed in primary tumours reveal gene signatures that predict clinical outcome in ER-positive disease exclusively. We find that the differential ER-binding programme observed in tumours from patients with poor outcome is not due to the selection of a rare subpopulation of cells, but is due to the FOXA1-mediated reprogramming of ER binding on a rapid timescale. The parallel redistribution of ER and FOXA1 binding events in drug-resistant cellular contexts is supported by histological co-expression of ER and FOXA1 in metastatic samples. By establishing transcription-factor mapping in primary tumour material, we show that there is plasticity in ER-binding capacity, with distinct combinations of cis-regulatory elements linked with the different clinical outcomes.
HART STEPHEN, ALI SIMAK, PUFONG BORIS TUMI, et al., 2011, Control of Gene Expression Using a Complex of an Oligonucleotide and a Regulatory Peptide
A method for suppressing the expression of a selected gene in a cell, the method comprising introducing into the cell a molecule comprising (1) a nucleic acid binding portion which binds to a site or associated with the selected gene which site is present in a genome and (2) an expression repressor portion, wherein the nucleic acid binding portion comprises an oligonucleotide or oligonucleotide mimic or analogue, and wherein the repressor portion comprises a polypeptide or peptidomimetic. Molecules for use in the methods of the invention are provided. The repressor may be a portion of a histone deacetylase or DNA methylase or polypeptide capable of recruiting a histone deacetylase or DNA methylase.
Patel BH, Mason AM, Patel H, et al., 2011, Conversion of alpha-Amino Acids into Bioactive o-Aminoalkyl Resorcylates and Related Dihydroxyisoindolinones, JOURNAL OF ORGANIC CHEMISTRY, Vol: 76, Pages: 6209-6217, ISSN: 0022-3263
Tolhurst RS, Thomas RS, Kyle FJ, et al., 2011, Transient over-expression of estrogen receptor-alpha in breast cancer cells promotes cell survival and estrogen-independent growth, BREAST CANCER RESEARCH AND TREATMENT, Vol: 128, Pages: 357-368, ISSN: 0167-6806
Thiruchelvam PTR, Lai C-F, Hua H, et al., 2011, The liver receptor homolog-1 regulates estrogen receptor expression in breast cancer cells, BREAST CANCER RESEARCH AND TREATMENT, Vol: 127, Pages: 385-396, ISSN: 0167-6806
Giamas G, Filipovic A, Messier W, et al., 2010, Kinome Screening for Regulators of Estrogen Receptor Identifies a Novel Kinase as a New Therapeutic Target in Breast Cancer.
Ali S, Buluwela L, Coombes RC, 2011, Antiestrogens and Their Therapeutic Applications in Breast Cancer and Other Diseases, ANNUAL REVIEW OF MEDICINE, VOL 62, 2011, Vol: 62, Pages: 217-232, ISSN: 0066-4219
Toumi M, Barbazanges M, Kroll SHB, et al., 2010, Concise, flexible syntheses of 4-(4-imidazolyl)pyrimidine cyclin-dependent kinase 2 (CDK2) inhibitors, TETRAHEDRON LETTERS, Vol: 51, Pages: 6126-6128, ISSN: 0040-4039
Buluwela L, Kamalati T, Photiou A, et al., 2010, A Simple Laboratory Practical to Illustrate RNA Mediated Gene Interference Using Drosophila Cell Culture, BIOCHEMISTRY AND MOLECULAR BIOLOGY EDUCATION, Vol: 38, Pages: 393-399, ISSN: 1470-8175
Ali S, Buluwela L, Coombes RC, Antiestrogens and their therapeutic applications in breast cancer and other diseases, Annu Rev Med, Vol: 62, Pages: 217-232
The identification of the link between breast cancer and estrogens has led to the development of antiestrogens, in particular tamoxifen, to inhibit the activities of estrogen receptors (ERs) in breast cancer cells. The clinical use of tamoxifen has played a major part in decreasing breast cancer mortality over the past 30 years. Though antiestrogenic in the breast, some antiestrogens have estrogen-like actions in other tissues, acting to promote bone density and protect against cardiovascular disease, thus raising the possibility of their use in counteracting the effects of estrogen loss following menopause. Moreover, antiestrogens show efficacy as chemopreventive agents in women at high risk of developing breast cancer. Thus, antiestrogens define an important and well-understood class of cancer drug, which continue to be a mainstay in breast cancer treatment.
Thiruchelvam PTR, Hua H, Lai CF, et al., 2010, Characterization of estrogen responses in breast cancer cell lines highlights ER alpha as an LRH-1 regulated gene, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
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