13 results found
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.
Fulton J, Harrod A, Van N, et al., 2016, Use of CRISPR-Cas9-mediated knockin mutagenesis of ESR1 mutations in metastatic breast cancer allow functional analysis and evaluation of treatment options, UK Breast Cancer Research Symposium, Publisher: SPRINGER, Pages: 193-193, ISSN: 0167-6806
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.
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
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
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
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
Thiruchelvam P, Photiou A, Fui LC, et al., 2009, Characterization of the nuclear receptor LRH-1 reveals a new form that can function in estrogen regulated breast cancer cell growth, CANCER RESEARCH, Vol: 69, ISSN: 0008-5472
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