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Search Results: 1 - 10 of 298156 matches for " Chad J Creighton "
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Multiple Oncogenic Pathway Signatures Show Coordinate Expression Patterns in Human Prostate Tumors
Chad J. Creighton
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0001816
Abstract: Background Gene transcription patterns associated with activation of oncogenes Myc, c-Src, beta-catenin, E2F3, H-Ras, HER2, EGFR, MEK, Raf, MAPK, Akt, and cyclin D1, as well as of the cell cycle and of androgen signaling have been generated in previous studies using experimental models. It was not clear whether genes in these “oncogenic signatures” would show coordinate expression patterns in human prostate tumors, particularly as most of the signatures were derived from cell types other than prostate. Principal Findings The above oncogenic pathway signatures were examined in four different gene expression profile datasets of human prostate tumors (representing ~250 patients in all), using both Q1-Q2 and one-sided Fisher's exact enrichment analysis methods. A significant fraction (~5%) of genes up-regulated experimentally by Myc, c-Src, HER2, Akt, or androgen were co-expressed in human tumors with the oncogene or biomarker corresponding to the pathway signature. Genes down-regulated experimentally, however, did not show anticipated patterns of anti-enrichment in the human tumors. Conclusions Significant subsets of the genes in these experimentally-derived oncogenic signatures are relevant to the study of human prostate cancer. Both molecular biologists and clinical researchers could focus attention on the relatively small number of genes identified here as having coordinate patterns that arise from both the experimental system and the human disease system.
A gene transcription signature associated with hormone independence in a subset of both breast and prostate cancers
Chad J Creighton
BMC Genomics , 2007, DOI: 10.1186/1471-2164-8-199
Abstract: From analyses of global gene expression profile data, a nonrandom amount of overlap was observed between the set of genes associated with estrogen receptor negative (ER-), hormone independent breast cancer and the set of genes associated with androgen independent (AI) prostate cancer. A set of 81 genes was identified that were differentially expressed between ER- and ER+ clinical breast tumors and breast cancer cell lines and that showed concordant expression in AI versus AS (androgen sensitive) prostate cell lines. This common gene signature of hormone independence was used to identify a subset of clinically localized primary prostate tumors that shared extensive similarities in gene transcription with both ER- breast and AI prostate cell lines and that tended to show concurrent deactivation of the androgen signaling pathway. Both ER- breast and AI prostate cell lines were significantly enriched for transcriptional targets of signaling via epidermal growth factor receptor (EGFR).This study indicates that the growth- and survival-promoting functions of hormone receptors can be bypassed in a subset of both breast and prostate cancers by the same growth factor signaling pathways, which holds implications for the use of targeted therapy regimens.In 2006, on the order of 234,000 men and 213,000 women were diagnosed with prostate cancer and breast cancer, respectively, and about 27,000 men and 41,000 women died (American Cancer Society statistics). Steroid hormone receptor signaling has been linked to all stages of prostate and breast carcinogenesis [1,2]. Initial treatment of clinically localized prostate cancer (PCA) and invasive breast cancer (IBC) usually involves surgical removal of the cancerous tissue or radiation therapy. The clinical use of adjuvant anti-androgen therapy in PCA and of anti-estrogen therapy in IBC has aided greatly in prolonging or preventing disease recurrence, as the majority of these cancers, at least initially, depend upon their associated ho
Widespread Molecular Patterns Associated with Drug Sensitivity in Breast Cancer Cell Lines, with Implications for Human Tumors
Chad J. Creighton
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0071158
Abstract: Background Recent landmark studies have profiled cancer cell lines for molecular features, along with measuring the corresponding growth inhibitory effects for specific drug compounds. These data present a tool for determining which subsets of human cancer might be more responsive to particular drugs. To this end, the NCI-DREAM-sponsored DREAM7: Drug Sensitivity Prediction Challenge (sub-challenge 1) set out to predict the sensitivities of 18 breast cancer cell lines to 31 previously untested compounds, on the basis of molecular profiling data and a training subset of cell lines. Methods and Results With 47 teams submitting blinded predictions, team Creighton scored third in terms of overall accuracy. Team Creighton's method was simple and straightforward, incorporated multiple expression data types (RNA-seq, gene array, RPPA), and incorporated all profiled features (not only the “best” predictive ones). As an extension of the approach, cell line data, from public datasets of expression profiling coupled with drug sensitivities (Barretina, Garnett, Heiser) were used to “predict” the drug sensitivities in human breast tumors (using data from The Cancer Genome Atlas). Drug sensitivity correlations within human breast tumors showed differences by expression-based subtype, with many associations in line with the expected (e.g. Lapatinib sensitivity in HER2-enriched cancers) and others inviting further study (e.g. relative resistance to PI3K inhibitors in basal-like cancers). Conclusions Molecular patterns associated with drug sensitivity are widespread, with potentially hundreds of genes that could be incorporated into making predictions, as well as offering biological clues as to the mechanisms involved. Applying the cell line patterns to human tumor data may help generate hypotheses on what tumor subsets might be more responsive to therapies, where multiple cell line datasets representing various drugs may be used, in order to assess consistency of patterns.
When will tumor gene expression profiling be incorporated into clinical breast cancer decision making?
Chad J Creighton, James M Rae
Breast Cancer Research , 2006, DOI: 10.1186/bcr1519
Abstract: Gene expression profiling of cancers has great potential as a valuable tool in the identification of new clinical biomarkers and of the molecular pathways that underlie the disease. Among other factors, expression profiling may uncover new molecular subtypes of breast cancer that transcend current histologic definitions. In a series of seminal studies conducted by Sorlie and coworkers [1], hierarchical clustering of breast tumor profiles from multiple independent datasets revealed a basal epithelial-like group, an ERBB2/HER2-overexpressing group, two distinct luminal-like groups, and a normal breast-like group. However, current histologic definitions of breast cancer largely reflect the tumor subtypes uncovered by Sorlie and colleagues; for instance, the basal tumors reflect the estrogen receptor (ER)-negative subtype, whereas the luminal tumors reflect the ER-positive subtype. It would be useful to know whether additional relevant subtypes of breast cancer may be uncovered, either by profiling larger cohorts of tumors or by using alternative data analysis approaches, with the ultimate goal of individualizing therapy based on the molecular profile of the patient's tumor. There is already established precedence for clinical use of molecular markers to help make decisions on the course of treatment in breast cancer, because expression of ER and progesterone receptor are used to assess the potential response to hormonal therapy, and expression of ERBB2/HER2 is used to assess potential response to herceptin.A number of studies have identified gene expression patterns in breast cancer with the ability to predict disease outcome. The first of these studies is that by van 't Veer and coworkers [2], in which a classifier of 70 genes was defined that outperformed all clinical variables in predicting the likelihood of distant metastases within 5 years. Van 't Veer and colleagues have formed a cancer diagnostics company [3], which provides a service called MammaPrint to assess
Stem Cell Antigen-1 (Sca-1) Regulates Mammary Tumor Development and Cell Migration
Torey D. Batts, Heather L. Machado, Yiqun Zhang, Chad J. Creighton, Yi Li, Jeffrey M. Rosen
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0027841
Abstract: Background Stem cell antigen-1 (Sca-1 or Ly6A) is a glycosyl phostidylinositol (GPI)-anchored cell surface protein associated with both stem and progenitor activity, as well as tumor initiating-potential. However, at present the functional role for Sca-1 is poorly defined. Methodology/Principal Findings To investigate the role of Sca-1 in mammary tumorigenesis, we used a mammary cell line derived from a MMTV-Wnt1 mouse mammary tumor that expresses high levels of endogenous Sca-1. Using shRNA knockdown, we demonstrate that Sca-1 expression controls cell proliferation during early tumor progression in mice. Functional limiting dilution transplantations into recipient mice demonstrate that repression of Sca-1 increases the population of tumor propagating cells. In scratch monolayer assays, Sca-1 enhances cell migration. In addition, knockdown of Sca-1 was shown to affect cell adhesion to a number of different extracellular matrix components. Microarray analysis indicates that repression of Sca-1 leads to changes in expression of genes involved in proliferation, cell migration, immune response and cell organization. Conclusions/Significance Sca-1 exerts marked effects on cellular activity and tumorgenicity both in vitro and in vivo. A better understanding of Sca-1 function may provide insight into the broader role of GPI-anchored cell surface proteins in cancer.
Transcriptional Profiling of Non-Small Cell Lung Cancer Cells with Activating EGFR Somatic Mutations
Kuicheon Choi, Chad J. Creighton, David Stivers, Nobukazu Fujimoto, Jonathan M. Kurie
PLOS ONE , 2007, DOI: 10.1371/journal.pone.0001226
Abstract: Background Activating somatic mutations in epidermal growth factor receptor (EGFR) confer unique biologic features to non-small cell lung cancer (NSCLC) cells, but the transcriptional mediators of EGFR in this subgroup of NSCLC have not been fully elucidated. Methodology/Principal Findings Here we used genetic and pharmacologic approaches to elucidate the transcriptomes of NSCLC cell lines. We transcriptionally profiled a panel of EGFR-mutant and -wild-type NSCLC cell lines cultured in the presence or absence of an EGFR tyrosine kinase inhibitor. Hierarchical analysis revealed that the cell lines segregated on the basis of EGFR mutational status (mutant versus wild-type), and expression signatures were identified by supervised analysis that distinguished the cell lines based on mutational status (wild-type versus mutant) and type of mutation (L858R versus Δ746-750). Using an EGFR mutation-specific expression signature as a probe, we mined the gene expression profiles of two independent cohorts of NSCLC patients and found the signature in a subset. EGFR tyrosine kinase inhibitor treatment regulated the expression of multiple genes, and pharmacologic inhibition of the protein products of two of them (PTGS2 and EphA2) inhibited anchorage-independent growth in EGFR-mutant NSCLC cells. Conclusions/Significance We have elucidated genes not previously associated with EGFR-mutant NSCLC, two of which enhanced the clonogenicity of these cells, distinguishing these mediators from others previously shown to maintain cell survival. These findings have potential clinical relevance given the availability of pharmacologic tools to inhibit the protein products of these genes.
miR-1 and miR-133b Are Differentially Expressed in Patients with Recurrent Prostate Cancer
Omer Faruk Karatas, Esra Guzel, Ilknur Suer, Isin D. Ekici, Turhan Caskurlu, Chad J. Creighton, Michael Ittmann, Mustafa Ozen
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0098675
Abstract: Prostate cancer (PCa) is currently the most frequently diagnosed malignancy in the western countries. It is more prevalent in older men with 75% of the incident cases above 65 years old. After radical prostatectomy, approximately 30% of men develop clinical recurrence with elevated serum prostate-specific antigen levels. Therefore, it is important to unravel the molecular mechanisms underlying PCa progression to develop novel diagnostic/therapeutic approaches. In this study, it is aimed to compare the microRNA (miRNA) profile of recurrent and non-recurrent prostate tumor tissues to explore the possible involvement of miRNAs in PCa progression. Total RNA from 41 recurrent and 41 non-recurrent PCa tissue samples were used to investigate the miRNA signature in PCa specimens. First of all, 20 recurrent and 20 non-recurrent PCa samples were profiled using miRNA microarray chips. Of the differentially expressed miRNAs, miR-1, miR-133b and miR-145* were selected for further validation with qRT-PCR in a different set of 21 recurrent and 21 non-recurrent PCa samples. Data were statistically analyzed using two-sided Student's t-test, Pearson Correlation test, Receiver operating characteristic analysis. Our results demonstrated that miR-1 and mir-133b have been significantly downregulated in recurrent PCa specimens in comparison to non-recurrent PCa samples and have sufficient power to distinguish recurrent specimens from non-recurrent ones on their own. Here, we report that the relative expression of miR-1 and mir-133b have been significantly reduced in recurrent PCa specimens in comparison to non-recurrent PCa samples, which can serve as novel biomarkers for prediction of PCa progression.
Pregnancy-Induced Noncoding RNA (PINC) Associates with Polycomb Repressive Complex 2 and Regulates Mammary Epithelial Differentiation
Amy N. Shore,Elena B. Kabotyanski,Kevin Roarty,Martin A. Smith,Yiqun Zhang,Chad J. Creighton,Marcel E. Dinger,Jeffrey M. Rosen
PLOS Genetics , 2012, DOI: 10.1371/journal.pgen.1002840
Abstract: Pregnancy-induced noncoding RNA (PINC) and retinoblastoma-associated protein 46 (RbAp46) are upregulated in alveolar cells of the mammary gland during pregnancy and persist in alveolar cells that remain in the regressed lobules following involution. The cells that survive involution are thought to function as alveolar progenitor cells that rapidly differentiate into milk-producing cells in subsequent pregnancies, but it is unknown whether PINC and RbAp46 are involved in maintaining this progenitor population. Here, we show that, in the post-pubertal mouse mammary gland, mPINC is enriched in luminal and alveolar progenitors. mPINC levels increase throughout pregnancy and then decline in early lactation, when alveolar cells undergo terminal differentiation. Accordingly, mPINC expression is significantly decreased when HC11 mammary epithelial cells are induced to differentiate and produce milk proteins. This reduction in mPINC levels may be necessary for lactation, as overexpression of mPINC in HC11 cells blocks lactogenic differentiation, while knockdown of mPINC enhances differentiation. Finally, we demonstrate that mPINC interacts with RbAp46, as well as other members of the polycomb repressive complex 2 (PRC2), and identify potential targets of mPINC that are differentially expressed following modulation of mPINC expression levels. Taken together, our data suggest that mPINC inhibits terminal differentiation of alveolar cells during pregnancy to prevent abundant milk production and secretion until parturition. Additionally, a PRC2 complex that includes mPINC and RbAp46 may confer epigenetic modifications that maintain a population of mammary epithelial cells committed to the alveolar fate in the involuted gland.
Expression Signatures of Metastatic Capacity in a Genetic Mouse Model of Lung Adenocarcinoma
Don L. Gibbons, Wei Lin, Chad J. Creighton, Shuling Zheng, Dror Berel, Yanan Yang, Maria Gabriela Raso, Diane D. Liu, Ignacio I. Wistuba, Guillermina Lozano, Jonathan M. Kurie
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0005401
Abstract: Background Non-small cell lung cancer (NSCLC) is the foremost cause of cancer-related death in Western countries, which is due partly to the propensity of NSCLC cells to metastasize. The biologic basis for NSCLC metastasis is not well understood. Methodology/Principal Findings Here we addressed this deficiency by transcriptionally profiling tumors from a genetic mouse model of human lung adenocarcinoma that develops metastatic disease owing to the expression of K-rasG12D and p53R172H. We identified 2,209 genes that were differentially expressed in distant metastases relative to matched lung tumors. Mining of publicly available data bases revealed this expression signature in a subset of NSCLC patients who had a poorer prognosis than those without the signature. Conclusions/Significance These findings provide evidence that K-rasG12D; p53R172H mice recapitulate features of human NSCLC metastasis and will provide a useful platform on which to study the biologic basis for lung adenocarcinoma metastasis and its prevention by novel agents.
Genes regulated by estrogen in breast tumor cells in vitro are similarly regulated in vivo in tumor xenografts and human breast tumors
Chad J Creighton, Kevin E Cordero, Jose M Larios, Rebecca S Miller, Michael D Johnson, Arul M Chinnaiyan, Marc E Lippman, James M Rae
Genome Biology , 2006, DOI: 10.1186/gb-2006-7-4-r28
Abstract: We generated DNA microarray-based gene expression profiles from three estrogen receptor α (ERα)-positive breast cancer cell lines stimulated by 17β-estradiol (E2) in vitro over a time course, as well as from MCF-7 cells grown as xenografts in ovariectomized athymic nude mice with E2 supplementation and after its withdrawal. When the patterns of genes regulated by E2 in vitro were compared to those obtained from xenografts, we found a remarkable overlap (over 40%) of genes regulated by E2 in both contexts. These patterns were compared to those obtained from published clinical data sets. We show that, as a group, E2-regulated genes from our preclinical models were co-expressed with ERα in a panel of ERα+ breast tumor mRNA profiles, when corrections were made for patient age, as well as with progesterone receptor. Furthermore, the E2-regulated genes were significantly enriched for transcriptional targets of the myc oncogene and were found to be coordinately expressed with Myc in human tumors.Our results provide significant validation of a widely used in vitro model of estrogen signaling as being pathologically relevant to breast cancers in vivo.Estrogenic hormones are key regulators of growth, differentiation, and function in a wide array of target tissues, including the male and female reproductive tracts, mammary gland, and skeletal and cardiovascular systems. Many of the effects of estrogens are mediated via their nuclear receptors, estrogen receptor (ER)α and ERβ. The estrogen receptors mediate a number of effects within the cell, mainly by altering the transcription of genes via direct interaction with their promoters or through binding to other proteins, which in turn interact with and regulate gene promoters [1]. It has been well-established that estrogen plays a significant role in breast cancer development and progression [2]. Increased lifetime exposure to estrogen is a factor in breast cancer risk [3], and drugs that block the effects of estrogen can inhibit
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