106 results found
HART STEPHEN GB, ALI SIMAK GB, PUFONG BORIS T GB, et al., 2023, Control of gene expression using a complex of an oligonucleotide and a regulatory peptide, US2005136040
Jurgaityte K, Sava G, Lai CF, et al., 2023, Defining modulators of response to samuraciclib, a CDK7 inhibitor for breast cancer, 114th Annual Meeting of the American Association for Cancer Research (AACR), Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Harrod A, Lai C, Goldsbrough I, et al., 2022, Genome engineering for estrogen receptor mutations reveals differential responses to anti-estrogens and new prognostic gene signatures for breast cancer, Oncogene, Vol: 41, Pages: 4905-4915, ISSN: 0950-9232
Mutations in the estrogen receptor (ESR1) gene are common in ER-positive breast cancer patients who progress on endocrine therapies. Most mutations localise to just three residues at, or near, the C-terminal helix 12 of the hormone binding domain, at leucine-536, tyrosine-537 and aspartate-538. To investigate these mutations, we have used CRISPR-Cas9 mediatedgenome engineering to generate a comprehensive set of isogenic mutant breast cancer cell lines. Our results confirm that L536R, Y537C, Y537N, Y537S and D538G mutations confer estrogen-independent growth in breast cancer cells. Growth assays show mutation-specific reductions in sensitivities to drugs representing three classes of clinical anti-estrogens. These differential mutation- and drug-selectivity profiles have implications for treatment choices following clinical emergence of ER mutations. Our results further suggest that mutant expression levels may be determinants of the degree of resistance to some anti-estrogens. Differential gene expression analysis demonstrates up-regulation of estrogen-responsivegenes, as expected, but also reveals that enrichment for interferon-regulated gene expression is a common feature of all mutations. Finally, a new gene signature developed from the geneexpression profiles in ER mutant cells predicts clinical response in breast cancer patients withER mutations
Li Z, McGinn O, Wu Y, et al., 2022, ESR1 mutant breast cancers show elevated basal cytokeratins and immune activation, Nature Communications, Vol: 13, Pages: 1-18, ISSN: 2041-1723
Estrogen receptor alpha (ER/ESR1) is frequently mutated in endocrine resistant ER-positive (ER+) breast cancer and linked to ligand-independent growth and metastasis. Despite the distinct clinical features of ESR1 mutations, their role in intrinsic subtype switching remains largely unknown. Here we find that ESR1 mutant cells and clinical samples show a significant enrichment of basal subtype markers, and six basal cytokeratins (BCKs) are the most enriched genes. Induction of BCKs is independent of ER binding and instead associated with chromatin reprogramming centered around a progesterone receptor-orchestrated insulated neighborhood. BCK-high ER+ primary breast tumors exhibit a number of enriched immune pathways, shared with ESR1 mutant tumors. S100A8 and S100A9 are among the most induced immune mediators and involve in tumor-stroma paracrine crosstalk inferred by single-cell RNA-seq from metastatic tumors. Collectively, these observations demonstrate that ESR1 mutant tumors gain basal features associated with increased immune activation, encouraging additional studies of immune therapeutic vulnerabilities.
Li Z, Wu Y, Yates ME, et al., 2022, Hotspot ESR1 mutations are multimodal and contextual modulators of breast cancer metastasis, Cancer Research, Vol: 82, Pages: 1321-1339, ISSN: 0008-5472
Constitutively active estrogen receptor α (ER/ESR1) mutations have been identified in approximately one-third of ER+ metastatic breast cancers. Although these mutations are known as mediators of endocrine resistance, their potential role in promoting metastatic disease has not yet been mechanistically addressed. In this study, we show the presence of ESR1 mutations exclusively in distant but not local recurrences in five independent breast cancer cohorts. In concordance with transcriptomic profiling of ESR1-mutant tumors, genome-edited ESR1 Y537S and D538G-mutant cell models exhibited a reprogrammed cell adhesive gene network via alterations in desmosome/gap junction genes and the TIMP3/MMP axis, which functionally conferred enhanced cell–cell contacts while decreasing cell-extracellular matrix adhesion. In vivo studies showed ESR1-mutant cells were associated with larger multicellular circulating tumor cell (CTC) clusters with increased compactness compared with ESR1 wild-type CTCs. These preclinical findings translated to clinical observations, where CTC clusters were enriched in patients with ESR1-mutated metastatic breast cancer. Conversely, context-dependent migratory phenotypes revealed cotargeting of Wnt and ER as a vulnerability in a D538G cell model. Mechanistically, mutant ESR1 exhibited noncanonical regulation of several metastatic pathways, including secondary transcriptional regulation and de novo FOXA1-driven chromatin remodeling. Collectively, these data provide evidence for ESR1 mutation–modulated metastasis and suggest future therapeutic strategies for targeting ESR1-mutant breast cancer.
Mayayo-Peralta I, Faggion B, Hoekman L, et al., 2021, Ribociclib induces broad chemotherapy resistance and EGFR dependency in ESR1 wildtype and mutant breast cancer, Cancers, Vol: 13, ISSN: 2072-6694
While endocrine therapy is highly effective for the treatment of oestrogen receptor-α (ERα)-positive breast cancer, a significant number of patients will eventually experience disease progression and develop treatment-resistant, metastatic cancer. The majority of resistant tumours remain dependent on ERα-action, with activating ESR1 gene mutations occurring in 15–40% of advanced cancers. Therefore, there is an urgent need to discover novel effective therapies that can eradicate cancer cells with aberrant ERα and to understand the cellular response underlying their action. Here, we evaluate the response of MCF7-derived, CRISPR-Cas9-generated cell lines expressing mutant ERα (Y537S) to a large number of drugs. We report sensitivity to numerous clinically approved inhibitors, including CDK4/6 inhibitor ribociclib, which is a standard-of-care therapy in the treatment of metastatic ERα-positive breast cancer and currently under evaluation in the neoadjuvant setting. Ribociclib treatment induces senescence in both wildtype and mutant ERα breast cancer models and leads to a broad-range drug tolerance. Strikingly, viability of cells undergoing ribociclib-induced cellular senescence is maintained via engagement of EGFR signalling, which may be therapeutically exploited in both wildtype and mutant ERα-positive breast cancer. Our study highlights a wide-spread reduction in sensitivity to anti-cancer drugs accompanied with an acquired vulnerability to EGFR inhibitors following CDK4/6 inhibitor treatment
Wu Y, Li Z, Bahreini A, et al., 2021, Neomorphic cell-cell adhesion reprogramming facilitates metastasis of <i>ESR1</i> mutant breast cancer., Annual Meeting of the American-Association-for-Cancer-Research (AACR), Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Li Z, Wu Y, Bahreini A, et al., 2021, Hotspot <i>ESR1</i> mutations rewire cell-cell adhesome to facilitate breast cancer metastasis, San Antonio Breast Cancer Virtual Symposium, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Periyasamy M, Singh A, Gemma C, et al., 2020, Induction of APOBEC3B expression by chemotherapy drugs is mediated by DNA-PK directed activation of NF-κB, Oncogene, Vol: 15 December 2020, Pages: 1077-1090, ISSN: 0950-9232
The mutagenic APOBEC3B (A3B) cytosine deaminase is frequently over-expressed in cancer and promotes tumour heterogeneity and therapy resistance. Hence, understanding the mechanisms that underlie A3B over-expression is important, especially for developing therapeutic approaches to reducing A3B levels, and consequently limiting cancer mutagenesis. We previously demonstrated that A3B is repressed by p53 and p53 mutation increases A3B expression. Here, we investigate A3B expression upon treatment with chemotherapeutic drugs that activate p53, including 5-fluorouracil, etoposide and cisplatin. Contrary to expectation, these drugs induced A3B expression and concomitant cellular cytosine deaminase activity. A3B induction was p53-independent, as chemotherapy drugs stimulated A3B expression in p53 mutant cells. These drugs commonly activate ATM, ATR and DNA-PKcs. Using specific inhibitors and gene knockdowns, we show that activation of DNA-PKcs and ATM by chemotherapeutic drugs promotes NF-kB activity, with consequent recruitment of NF-kB to the A3B gene promoter to drive A3B expression. Further, we find that A3B knockdown re-sensitises resistant cells to cisplatin, and A3B knockout enhances sensitivity to chemotherapy drugs. Our data highlight a role for A3B in resistance to chemotherapy and indicate that stimulation of A3B expression by activation of DNA repair and NF-kB pathways could promote cancer mutations and expedite chemoresistance.
Cyclin-dependent kinase 7 (CDK7), along with cyclin H and MAT1, forms the CDK-activating complex (CAK), which directs progression through the cell cycle via T-loop phosphorylation of cell cycle CDKs. CAK is also a component of the general transcription factor, TFIIH. CDK7-mediated phosphorylation of RNA polymerase II (Pol II) at active gene promoters permits transcription. Cell cycle dysregulation is an established hallmark of cancer, and aberrant control of transcriptional processes, through diverse mechanisms, is also common in many cancers. Furthermore, CDK7 levels are elevated in a number of cancer types and are associated with clinical outcomes, suggestive of greater dependence on CDK7 activity, compared with normal tissues. These findings identify CDK7 as a cancer therapeutic target, and several recent publications report selective CDK7 inhibitors (CDK7i) with activity against diverse cancer types. Preclinical studies have shown that CDK7i cause cell cycle arrest, apoptosis and repression of transcription, particularly of super-enhancer-associated genes in cancer, and have demonstrated their potential for overcoming resistance to cancer treatments. Moreover, combinations of CDK7i with other targeted cancer therapies, including BET inhibitors, BCL2 inhibitors and hormone therapies, have shown efficacy in model systems. Four CDK7i, ICEC0942 (CT7001), SY-1365, SY-5609 and LY3405105, have now progressed to Phase I/II clinical trials. Here we describe the work that has led to the development of selective CDK7i, the current status of the most advanced clinical candidates, and discuss their potential importance as cancer therapeutics, both as monotherapies and in combination settings. ClinicalTrials.gov Identifiers: NCT03363893; NCT03134638; NCT04247126; NCT03770494.
Sava G, Fan H, Fisher R, et al., 2020, ABC transporter upregulation mediates resistance to the CDK7 inhibitors THZ1 and ICEC0942., Oncogene, Vol: 39, Pages: 651-663, ISSN: 0950-9232
The CDK7 inhibitors (CDK7i) ICEC0942 and THZ1, are promising new cancer therapeutics. Resistance to targeted drugs frequently compromises cancer treatment. We sought to identify mechanisms by which cancer cells may become resistant to CDK7i. Resistant lines were established through continuous drug selection. ABC-transporter copy number, expression and activity were examined using real-time PCR, immunoblotting and flow cytometry. Drug responses were measured using growth assays. ABCB1 was up-regulated in ICEC0942-resistant cells and there was cross-resistance to THZ1. THZ1-resistant cells upregulated ABCG2 but remained sensitive to ICEC0942. Drug resistance in both cell lines was reversible upon inhibition of ABC-transporters. CDK7i response was altered in adriamycin- and mitoxantrone-resistant cell lines demonstrating ABC-transporter upregulation. ABCB1 expression correlated with ICEC0942 and THZ1 response, and ABCG2 expression with THZ2 response, in a panel of cancer cell lines. We have identified ABCB1 upregulation as a common mechanism of resistance to ICEC0942 and THZ1, and confirmed that ABCG2 upregulation is a mechanism of resistance to THZ1. The identification of potential mechanisms of CDK7i resistance and differences in susceptibility of ICEC0942 and THZ1 to ABC-transporters, may help guide their future clinical use.
Ali S, Patel H, Periyasamy M, et al., 2018, ICEC0942, an orally bioavailable selective inhibitor of CDK7 for cancer treatment, Molecular Cancer Therapeutics, ISSN: 1535-7163
Recent reports indicate that some cancer types are especially sensitive to transcription inhibition, suggesting that targeting the transcriptional machinery provides new approaches to cancer treatment. Cyclin-dependent kinase (CDK)7 is necessary for transcription, and acts by phosphorylating the C-terminal domain (CTD) of RNA polymerase II (PolII) to enable transcription initiation. CDK7 additionally regulates the activities of a number of transcription factors, including Estrogen receptor-α (ER). Here we describe a new, orally bioavailable CDK7 inhibitor, ICEC0942. It selectively inhibits CDK7, with an IC50 of 40nM; IC50 values for CDK1, CDK2, CDK5 and CDK9 were 45-, 15-, 230- and 30-fold higher. In vitro studies show that a wide range of cancer types are sensitive to CDK7 inhibition with GI50 values ranging between 0.2-0.3 µM. In xenografts of both breast and colorectal cancers, the drug has substantial anti-tumor effects. Additionally, combination therapy with tamoxifen showed complete growth arrest of ER-positive tumor xenografts. Our findings reveal that CDK7 inhibition provides a new approach, especially for ER-positive breast cancer and identify ICEC0942 as a prototype drug with potential utility as a single agent or in combination with hormone therapies for breast cancer. ICEC0942 may also be effective in other cancers that display characteristics of transcription factor addiction, such as acute leukaemia, and small-cell lung cancer.
Martin L-A, Ribas R, Simigdala N, et al., 2017, Discovery of naturally occurring ESR1 mutations in breast cancer cell lines modelling endocrine resistance., Nature Communications, Vol: 8, ISSN: 2041-1723
Resistance to endocrine therapy remains a major clinical problem in breast cancer. Genetic studies highlight the potential role of estrogen receptor-α (ESR1) mutations, which show increased prevalence in the metastatic, endocrine-resistant setting. No naturally occurring ESR1 mutations have been reported in in vitro models of BC either before or after the acquisition of endocrine resistance making functional consequences difficult to study. We report the first discovery of naturally occurring ESR1 Y537C and ESR1 Y537S mutations in MCF7 and SUM44 ESR1-positive cell lines after acquisition of resistance to long-term-estrogen-deprivation (LTED) and subsequent resistance to fulvestrant (ICIR). Mutations were enriched with time, impacted on ESR1 binding to the genome and altered the ESR1 interactome. The results highlight the importance and functional consequence of these mutations and provide an important resource for studying endocrine resistance.
Smith L, Farzan R, Ali S, et al., 2017, Author Correction: The responses of cancer cells to PLK1 inhibitors reveal a novel protective role for p53 in maintaining centrosome separation, Scientific Reports, Vol: 8, ISSN: 2045-2322
The original version of this Article contained a typographical error in the spelling of the author Adrian T. Saurin, which was incorrectly given as Adrian Saurin. This has now been corrected in the PDF and HTML versions of the Article, and in the accompanying Supplementary Material.
Smith L, Farzan R, Ali S, et al., 2017, The responses of cancer cells to PLK1 inhibitors reveal a novel protective role for p53 in maintaining centrosome separation., Scientific Reports, Vol: 7, ISSN: 2045-2322
Polo-like kinase-1 (PLK1) plays a major role in driving mitotic events, including centrosome disjunction and separation, and is frequently over-expressed in human cancers. PLK1 inhibition is a promising therapeutic strategy and works by arresting cells in mitosis due to monopolar spindles. The p53 tumour suppressor protein is a short-lived transcription factor that can inhibit the growth, or stimulate the death, of developing cancer cells. Curiously, although p53 normally acts in an anti-cancer capacity, it can offer significant protection against inhibitors of PLK1, but the events underpinning this effect are not known. Here, we show that functional p53 reduces the sensitivity to PLK1 inhibitors by permitting centrosome separation to occur, allowing cells to traverse mitosis and re-enter cycle with a normal complement of 2N chromosomes. Protection entails the activation of p53 through the DNA damage-response enzymes, ATM and ATR, and requires the phosphorylation of p53 at the key regulatory site, Ser15. These data highlight a previously unrecognised link between p53, PLK1 and centrosome separation that has therapeutic implications for the use of PLK1 inhibitors in the clinic.
Periyasamy M, Singh A, Gemma C, et al., 2017, p53 controls expression of the DNA deaminase APOBEC3B to limit its potential mutagenic activity in cancer cells, Nucleic Acids Research, Vol: 45, Pages: 11056-11069, ISSN: 1362-4962
Cancer genome sequencing has implicated the cytosine deaminase activity of apolipoprotein B mRNA editing enzyme catalytic polypeptide-like (APOBEC) genes as an important source of mutations in diverse cancers, with APOBEC3B (A3B) expression especially correlated with such cancer mutations. To better understand the processes directing A3B over-expression in cancer, and possible therapeutic avenues for targeting A3B, we have investigated the regulation of A3B gene expression. Here, we show that A3B expression is inversely related to p53 status in different cancer types and demonstrate that this is due to a direct and pivotal role for p53 in repressing A3B expression. This occurs through the induction of p21 (CDKN1A) and the recruitment of the repressive DREAM complex to the A3B gene promoter, such that loss of p53 through mutation, or human papilloma virus-mediated inhibition, prevents recruitment of the complex, thereby causing elevated A3B expression and cytosine deaminase activity in cancer cells. As p53 is frequently mutated in cancer, our findings provide a mechanism by which p53 loss can promote cancer mutagenesis.
Stavraka C, Mura M, Fischer R, et al., 2017, Protein interactions involving LARP1 in chemotherapy resistant ovarian cancer cells, Cancer Research, Vol: 77, Pages: B44-B44, ISSN: 1538-7445
Harrod A, Fulton J, Nguyen VTM, et al., 2016, Genomic modelling of the ESR1 Y537S mutation for evaluating function and new therapeutic approaches for metastatic breast cancer, Oncogene, Vol: 36, Pages: 2286-2296, ISSN: 1476-5594
Drugs that inhibit estrogen receptor-α (ER) activity have been highlysuccessful in treating and reducing breast cancer progression in ER-positivedisease. However, resistance to these therapies presents a major clinicalproblem. Recent genetic studies have shown that mutations in the ER geneare found in >20% of tumours that progress on endocrine therapies.Remarkably, the great majority of these mutations localise to just a few aminoacids within or near the critical helix 12 region of the ER hormone bindingdomain, where they are likely to be single allele mutations. Understandinghow these mutations impact on ER function is a prerequiste for identifyingmethods to treat breast cancer patients featuring such mutations. Towardsthis end, we used CRISPR-Cas9 genome editing to make a single alleleknockin of the most commonly mutated amino acid residue, tyrosine 537, inthe estrogen-responsive MCF7 breast cancer cell line. Genomic analysesusing RNA-seq and ER ChIP-seq demonstrated that the Y537S mutationpromotes constitutive ER activity globally, resulting in estrogen-independentgrowth. MCF7-Y537S cells were resistant to the anti-estrogen tamoxifen andfulvestrant. Further, we show that the basal transcription factor TFIIH isconstitutively recruited by ER-Y537S, resulting in ligand-independentphosphorylation of Serine 118 (Ser118) by the TFIIH kinase, CDK7. TheCDK7 inhibitor, THZ1 prevented Ser118 phosphorylation and inhibited growthof MCF7-Y537S cells. These studies confirm the functional importance of ERmutations in endocrine resistance, demonstrate the utility of knockinmutational models for investigating alternative therapeutic approaches andhighlight CDK7 inhibition as a potential therapy for endocrine resistant breastcancer mediated by ER mutations.
Ali S, Patel H, Periyasamy M, et al., 2016, ICEC0942, an orally bioavailable selective inhibitor of CDK7 for breast cancer, UK Breast Cancer Research Symposium, Publisher: Springer Verlag, Pages: 195-195, ISSN: 0167-6806
Aleskandarany MA, Abduljabbar R, Ashankyty I, et al., 2016, Prognostic significance of androgen receptor expression in invasive breast cancer: transcriptomic and protein expression analysis, Breast Cancer Research and Treatment, Vol: 159, Pages: 215-227, ISSN: 1573-7217
Differential prognostic roles of Androgen Receptor (AR) have been proposed in breast cancer (BC) depending on tumour oestrogen receptor (ER) status. This study aimed to evaluate the prognostic and/or predictive significance of AR expression in invasive BC. In this study AR expression was studied on a large (n = 1141) consecutive series of early-stage (I-III) BC using tissue microarray and immunohistochemistry (IHC). AR mRNA expression was assessed in a subset of cases. The prognostic impact of AR mRNA expression was externally validated using the online BC gene expression data sets (n = 25 data sets, 4078 patients). Nuclear AR IHC expression was significantly associated with features of good prognosis including older age, smaller tumour size, lower grade and lobular histology particularly in the ER-positive tumours. AR was associated with ER-related markers GATA3, FOXa1, RERG and BEX1. Negative association was observed with HER2, p53, Ki67, TK1, CD71 and AGTR1. AR Overexpression was associated with longer survival (p < 0.001), independent of tumour size, grade, stage [p = 0.033, hazard ratio (HR) = 0.80 95 % CI = 0.64-0.98]. Similar associations were maintained in ER+ tumours in univariate and multivariate analysis (p < 0.01) both in patients with and without adjuvant endocrine or chemotherapy. AR mRNA expression showed significant association with tumour grade, molecular subtypes, and longer 10 and 15 years survival in luminal BC. In the external validation cohorts, AR gene expression data were associated with improved patients' outcome (p < 0.001, HR = 0.84, 95 % CI 0.79-0.90). AR is not only an independent prognostic factor in ER-positive luminal BC but is also expressed in ER-negative tumours. AR could act as a molecular target in patients with ER-positive disease predicting response to adjuvant therapy.
Periyasamy M, Nguyen VTM, Patel H, et al., 2016, Cytidine deamination activity of APOBEC3B regulates estrogen receptor function in breast cancer, UK Breast Cancer Research Symposium, Publisher: Springer Verlag (Germany), Pages: 197-197, ISSN: 1573-7217
Patel H, Abduljabbar R, Lai CF, et al., 2016, CDK7, cyclin H and MAT1 is elevated in breast cancer and is prognostic in estrogen receptor- positive breast cancer, Clinical Cancer Research, Vol: 22, Pages: 5929-5938, ISSN: 1557-3265
PURPOSE: CDK-activation kinase (CAK) is required for the regulation of the cell-cycle and is a trimeric complex consisting of Cyclin Dependent Kinase 7 (CDK7), Cyclin H and the accessory protein, MAT1. CDK7 also plays a critical role in regulating transcription, primarily by phosphorylating RNA polymerase II, as well as transcription factors such as estrogen receptor-alpha(ERalpha).). Deregulation of cell cycle and transcriptional control is aare general featurefeatures of cancertumor cells, highlighting the potential for the use of CDK7 inhibitors as novel cancer therapeutics in cancer. EXPERIMENTAL DESIGN: mRNA and protein expression of CDK7 and its essential co-factors cyclinH and MAT1, were evaluated in breast cancer samples to determine if their levels are altered in cancer. Immunohistochemical staining of >900 breast cancers was used to determine the association with clinicopathological features and patient outcome. RESULTS: We show that expression of CDK7, cyclinH and MAT1 are all closely linked at the mRNA and protein level and their expression is elevated in breast cancer compared with the normal breast tissue. Intriguingly, CDK7 expression was inversely proportional to tumour grade and size and outcome analysis showed an association between CAK levels and better outcome. Moreover, CDK7 expression was positively associated with ERalpha expression and in particular with phosphorylation of ERalpha at serine 118, a site important for ERalpha transcriptional activity. CONCLUSIONS: Expression of components of the CAK complex, CDK7, MAT1 and Cyclin H are elevated in breast cancer and correlates with ERalpha.. Like ERalpha, CDK7 expression is inversely proportional to poor prognostic factors and survival.
Periyasamy M, Patel H, Lai C-F, 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.
Xu Y, Zhang H, Van TMN, et al., 2015, LMTK3 represses tumor suppressor-like genes through chromatin remodeling in breast cancer, Cell Reports, Vol: 12, Pages: 837-849, ISSN: 2211-1247
LMTK3 is an oncogenic receptor tyrosine kinase (RTK) implicated in various types of cancer, including breast, lung, gastric, and colorectal cancer. It is localized in different cellular compartments, but its nuclear function has not been investigated so far. We mapped LMTK3 binding across the genome using ChIP-seq and found that LMTK3 binding events are correlated with repressive chromatin markers. We further identified KRAB-associated protein 1 (KAP1) as a binding partner of LMTK3. The LMTK3/KAP1 interaction is stabilized by PP1α, which suppresses KAP1 phosphorylation specifically at LMTK3-associated chromatin regions, inducing chromatin condensation and resulting in transcriptional repression of LMTK3-bound tumor suppressor-like genes. Furthermore, LMTK3 functions at distal regions in tethering the chromatin to the nuclear periphery, resulting in H3K9me3 modification and gene silencing. In summary, we propose a model where a scaffolding function of nuclear LMTK3 promotes cancer progression through chromatin remodeling.
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
Varga A, Jenes A, Marczylo TH, et al., 2014, Anandamide produced by Ca<SUP>2+</SUP>-insensitive enzymes induces excitation in primary sensory neurons, PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY, Vol: 466, Pages: 1421-1435, ISSN: 0031-6768
Mistry S, Paule CC, Varga A, et al., 2014, Prolonged exposure to bradykinin and prostaglandin E2 increases TRPV1 mRNA but does not alter TRPV1 and TRPV1b protein expression in cultured rat primary sensory neurons, NEUROSCIENCE LETTERS, Vol: 564, Pages: 89-93, ISSN: 0304-3940
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