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  • 1
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    Crosstalk between lysine-specific demethylase 1 (LSD1) and histone deacetylases mediates antineoplastic efficacy of HDAC inhibitors in human breast cancer cells (2013)
    Oxford University Press
    Details
    Publication Date: 2013-06-04
    Description: Our previous studies demonstrated that lysine-specific demethylase 1 (LSD1) and histone deacetylases (HDACs) closely interact in controlling growth of breast cancer cells. However, the underlying mechanisms are largely unknown. In this study, we showed that knockdown of LSD1 expression (LSD1-KD) by RNAi decreased mRNA levels of HDAC isozymes in triple-negative breast cancer (TNBC) cells. Small interfering RNA (siRNA)-mediated depletion of HDAC5 expression induced the most significant accumulation of H3K4me2, a specific substrate of LSD1. Combined treatment with LSD1 inhibitor, pargyline, and HDAC inhibitor, SAHA (Vorinostat), led to superior growth inhibition and apoptotic death in TNBC cells, but exhibited additive or antagonistic effect on growth inhibition in non-TNBC counterparts or non-tumorigenic breast cells. Additionally, LSD1-KD enhanced SAHA-induced reexpression of a subset of aberrantly silenced genes, such as NR4A1, PCDH1, RGS16, BIK, and E-cadherin whose reexpression may be tumor suppressive. Genome-wide microarray study in MDA-MB-231 cells identified a group of tumor suppressor genes whose expression was induced by SAHA and significantly enhanced by LSD1-KD. We also showed that concurrent depletion of RGS16 by siRNA reduced overall cytotoxicity of SAHA and blocked the reexpression of E-cadherin, CDKN1C and ING1 in LSD1-deficient MDA-MB-231 cells. Furthermore, cotreatment with RGS16 siRNA reversed the downregulation of nuclear factor-kappaB expression induced by combined inhibition of LSD1 and HDACs, suggesting a crucial role of RGS16 in controlling key pathways of cell death in response to combination therapy. Taken together, these results provide novel mechanistic insight into the breast cancer subtype-dependent role of LSD1 in mediating HDAC activity and therapeutic efficacy of HDAC inhibitor.
    Print ISSN: 0143-3334
    Electronic ISSN: 1460-2180
    Topics: Medicine
    Published by Oxford University Press
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  • 2
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    Estrogen represses gene expression through reconfiguring chromatin structures (2013)
    Oxford University Press
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    Publication Date: 2013-09-26
    Description: Estrogen regulates over a thousand genes, with an equal number of them being induced or repressed. The distinct mechanisms underlying these dual transcriptional effects remain largely unknown. We derived comprehensive views of the transcription machineries assembled at estrogen-responsive genes through integrating multiple types of genomic data. In the absence of estrogen, the majority of genes formed higher-order chromatin structures, including DNA loops tethered to protein complexes involving RNA polymerase II (Pol II), estrogen receptor alpha (ERα) and ERα-pioneer factors. Genes to be ‘repressed’ by estrogen showed active transcription at promoters and throughout the gene bodies; genes to be ‘induced’ exhibited active transcription initiation at promoters, but with transcription paused in gene bodies. In the presence of estrogen, the majority of estrogen-induced genes retained the original higher-order chromatin structures, whereas most estrogen-repressed genes underwent a chromatin reconfiguration. For estrogen-induced genes, estrogen enhances transcription elongation, potentially through recruitment of co-activators or release of co-repressors with unique roles in elongation. For estrogen-repressed genes, estrogen treatment leads to chromatin structure reconfiguration, thereby disrupting the originally transcription-efficient chromatin structures. Our in silico studies have shown that estrogen regulates gene expression, at least in part, through modifying previously assembled higher-order complexes, rather than by facilitating de novo assembly of machineries.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 3
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    The search for ESR1 mutations in breast cancer (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-11-26
    Description: Nature Genetics 45, 1415 (2013). doi:10.1038/ng.2831 Authors: Steffi Oesterreich & Nancy E Davidson Two new studies report the identification of activating ESR1 gene mutations in aromatase inhibitor–resistant metastatic breast cancers. This insight into therapeutic resistance suggests new approaches that may be useful in the management of endocrine-resistant breast cancer.
    Print ISSN: 1061-4036
    Electronic ISSN: 1546-1718
    Topics: Biology , Medicine
    Published by Nature Publishing Group (NPG)
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  • 4
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    The Scaffold attachment factor b1 (Safb1) regulates myogenic differentiation by facilitating the transition of myogenic gene chromatin from a repressed to an activated state (2013)
    Oxford University Press
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    Publication Date: 2013-06-08
    Description: The regulation of skeletal muscle gene expression during myogenesis is mediated by lineage-specific transcription factors in combination with numerous cofactors, many of which modify chromatin structure. However, the involvement of scaffolding proteins that organize chromatin and chromatin-associated regulatory proteins has not extensively been explored in myogenic differentiation. Here, we report that Scaffold attachment factor b1 (Safb1), primarily associated with transcriptional repression, functions as a positive regulator of myogenic differentiation. Knockdown of Safb1 inhibited skeletal muscle marker gene expression and differentiation in cultured C2C12 myoblasts. In contrast, over-expression resulted in the premature expression of critical muscle structural proteins and formation of enlarged thickened myotubes. Safb1 co-immunoprecipitated with MyoD and was co-localized on myogenic promoters. Upon Safb1 knockdown, the repressive H3K27me3 histone mark and binding of the Polycomb histone methyltransferase Ezh2 persisted at differentiation-dependent gene promoters. In contrast, the appearance of histone marks and regulators associated with myogenic gene activation, such as myogenin and the SWI/SNF chromatin remodelling enzyme ATPase, Brg1, was blocked. These results indicate that the scaffold protein Safb1 contributes to the activation of skeletal muscle gene expression during myogenic differentiation by facilitating the transition of promoter sequences from a repressive chromatin structure to one that is transcriptionally permissive.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 5
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    Zoledronic acid effectiveness against breast cancer metastases - a role for estrogen in the microenvironment? (2012)
    BioMed Central
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    Publication Date: 2012-09-25
    Description: Zoledronic acid (ZA) is an imidazole-containing bisphosphonate which has been extensively studied as an osteoclast inhibitor. It decreases bone turnover and has been effective in limiting osteolysis in metastatic cancers, including breast cancer. Recent clinical trials that demonstrated enhancement of disease-free survival by bisphosphonates have prompted interest in bisphosphonates as anti-cancer agents. ZA, for example, increased disease-free survival in postmenopausal and in premenopausal, hormone-suppressed breast cancer patients. Intriguingly, however, there was a lack of an anti-cancer effect of ZA in premenopausal women without ovarian suppression. These observations have prompted the conjecture that anticancer effects of ZA are limited to "estrogen-poor environments". This review explores possible mechanisms compatible with differences in ZA activity in premenopausal compared with postmenopausal (or hormone-suppressed) women.
    Print ISSN: 1465-5411
    Electronic ISSN: 1465-542X
    Topics: Medicine
    Published by BioMed Central
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  • 6
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    To bind or not to bind - FoxA1 determines estrogen receptor action in breast cancer progression (2012)
    BioMed Central
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    Publication Date: 2012-06-20
    Description: Chromatin immunoprecipitation followed by massively parallel sequencing (ChIP-seq) is rapidly enabling the comprehensive characterization of genome-wide transcription factor-binding sites, thus defining the cistrome (cis-acting DNA targets of a trans-acting factor). Estrogen receptor (ER) ChIP-seq studies have been performed mainly in cell lines, but Ross-Innes and colleagues have now completed the first such study in clinical breast cancer samples. The study aimed at determining the dynamics of ER binding and differences between more and less aggressive primary breast tumors and metastases. The authors found that ER bound to DNA in both aggressive and drug-resistant tumors but to different sites and with different affinities. Given previous findings from cell lines, FoxA1 appears to play a critical role in this reprogramming of ER binding.
    Print ISSN: 1465-5411
    Electronic ISSN: 1465-542X
    Topics: Medicine
    Published by BioMed Central
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  • 7
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    Bias correction for selecting the minimal-error classifier from many machine learning models (2014)
    Oxford University Press
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    Publication Date: 2014-11-07
    Description: Motivation: Supervised machine learning is commonly applied in genomic research to construct a classifier from the training data that is generalizable to predict independent testing data. When test datasets are not available, cross-validation is commonly used to estimate the error rate. Many machine learning methods are available, and it is well known that no universally best method exists in general. It has been a common practice to apply many machine learning methods and report the method that produces the smallest cross-validation error rate. Theoretically, such a procedure produces a selection bias. Consequently, many clinical studies with moderate sample sizes (e.g. n = 30–60) risk reporting a falsely small cross-validation error rate that could not be validated later in independent cohorts. Results: In this article, we illustrated the probabilistic framework of the problem and explored the statistical and asymptotic properties. We proposed a new bias correction method based on learning curve fitting by inverse power law (IPL) and compared it with three existing methods: nested cross-validation, weighted mean correction and Tibshirani-Tibshirani procedure. All methods were compared in simulation datasets, five moderate size real datasets and two large breast cancer datasets. The result showed that IPL outperforms the other methods in bias correction with smaller variance, and it has an additional advantage to extrapolate error estimates for larger sample sizes, a practical feature to recommend whether more samples should be recruited to improve the classifier and accuracy. An R package ‘MLbias’ and all source files are publicly available. Availability and implementation: tsenglab.biostat.pitt.edu/software.htm. Contact: ctseng@pitt.edu Supplementary information: Supplementary data are available at Bioinformatics online.
    Print ISSN: 1367-4803
    Electronic ISSN: 1460-2059
    Topics: Biology , Computer Science , Medicine
    Published by Oxford University Press
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  • 8
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    Aromatase inhibitor-induced modulation of breast density: clinical and genetic effects (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-10-31
    Description: Aromatase inhibitor-induced modulation of breast density: clinical and genetic effects British Journal of Cancer 109, 2331 (29 October 2013). doi:10.1038/bjc.2013.587 Authors: N L Henry, H-P Chan, J Dantzer, C P Goswami, L Li, T C Skaar, J M Rae, Z Desta, N Khouri, R Pinsky, S Oesterreich, C Zhou, L Hadjiiski, S Philips, J Robarge, A T Nguyen, A M Storniolo, D A Flockhart, D F Hayes, M A Helvie & V Stearns
    Keywords: breast canceraromatase inhibitorbreast densitymammogrampolymorphism
    Print ISSN: 0007-0920
    Electronic ISSN: 1532-1827
    Topics: Medicine
    Published by Nature Publishing Group (NPG)
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  • 9
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    Scaffold attachment factor B1 regulates the androgen receptor in concert with the growth inhibitory kinase MST1 and the methyltransferase EZH2 (2014)
    Nature Publishing Group (NPG)
    In: Oncogene
    Details
    Publication Date: 2014-06-20
    Description: Scaffold attachment factor B1 regulates the androgen receptor in concert with the growth inhibitory kinase MST1 and the methyltransferase EZH2 Oncogene 33, 3235 (19 June 2014). doi:10.1038/onc.2013.294 Authors: N K Mukhopadhyay, J Kim, S You, M Morello, M H Hager, W-C Huang, A Ramachandran, J Yang, B Cinar, M A Rubin, R M Adam, S Oesterreich, D Di Vizio & M R Freeman
    Keywords: ARMST1/STK4Hippo-RASSF1-LATSprostate cancercastration resistance
    Print ISSN: 0950-9232
    Topics: Medicine
    Published by Nature Publishing Group (NPG)
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  • 10
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    Endocrine Response and Resistance in ILC (2014)
    The American Association for Cancer Research (AACR)
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    Publication Date: 2014-03-04
    Description: Invasive lobular carcinoma (ILC) is a histologic subtype of breast cancer that is frequently associated with favorable outcomes, as approximately 90% of ILC express the estrogen receptor (ER). However, recent retrospective analyses suggest that patients with ILC receiving adjuvant endocrine therapy may not benefit as much as patients with invasive ductal carcinoma. On the basis of these observations, we characterized ER function and endocrine response in ILC models. The ER-positive ILC cell lines MDA MB 134VI (MM134) and SUM44PE were used to examine the ER-regulated transcriptome via gene expression microarray analyses and ER ChIP-Seq, and to examine response to endocrine therapy. In parallel, estrogen response was assessed in vivo in the patient-derived ILC xenograft HCI-013. We identified 915 genes that were uniquely E2 regulated in ILC cell lines versus other breast cancer cell lines, and a subset of these genes were also E2 regulated in vivo in HCI-013. MM134 cells were de novo tamoxifen resistant and were induced to grow by 4-hydroxytamoxifen, as well as other antiestrogens, as partial agonists. Growth was accompanied by agonist activity of tamoxifen on ER-mediated gene expression. Though tamoxifen induced cell growth, MM134 cells required fibroblast growth factor receptor (FGFR)-1 signaling to maintain viability and were sensitive to combined endocrine therapy and FGFR1 inhibition. Our observation that ER drives a unique program of gene expression in ILC cells correlates with the ability of tamoxifen to induce growth in these cells. Targeting growth factors using FGFR1 inhibitors may block survival pathways required by ILC and reverse tamoxifen resistance. Cancer Res; 74(5); 1463–74. ©2014 AACR.
    Print ISSN: 0008-5472
    Electronic ISSN: 1538-7445
    Topics: Medicine
    Published by The American Association for Cancer Research (AACR)
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