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102. Cervical Cancer, Version 3.2019, NCCN Clinical Practice Guidelines in Oncology

Author

Koh, Wui-Jin, primary, Abu-Rustum, Nadeem R., additional, Bean, Sarah, additional, Bradley, Kristin, additional, Campos, Susana M., additional, Cho, Kathleen R., additional, Chon, Hye Sook, additional, Chu, Christina, additional, Clark, Rachel, additional, Cohn, David, additional, Crispens, Marta Ann, additional, Damast, Shari, additional, Dorigo, Oliver, additional, Eifel, Patricia J., additional, Fisher, Christine M., additional, Frederick, Peter, additional, Gaffney, David K., additional, Han, Ernest, additional, Huh, Warner K., additional, Lurain, John R., additional, Mariani, Andrea, additional, Mutch, David, additional, Nagel, Christa, additional, Nekhlyudov, Larissa, additional, Fader, Amanda Nickles, additional, Remmenga, Steven W., additional, Reynolds, R. Kevin, additional, Tillmanns, Todd, additional, Ueda, Stefanie, additional, Wyse, Emily, additional, Yashar, Catheryn M., additional, McMillian, Nicole R., additional, and Scavone, Jillian L., additional

Published
2019
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104. Comparison of seven methods for producing Affymetrix expression scores based on False Discovery Rates in disease profiling data

Author

Gruber Stephen B, Giordano Thomas J, Cho Kathleen R, Macdonald James, Ghosh Debashis, Kuick Rork, Chen Wei, Shedden Kerby, Fearon Eric R, Taylor Jeremy MG, and Hanash Samir

Subjects
Computer applications to medicine. Medical informatics, R858-859.7, Biology (General), QH301-705.5
Abstract

Abstract Background A critical step in processing oligonucleotide microarray data is combining the information in multiple probes to produce a single number that best captures the expression level of a RNA transcript. Several systematic studies comparing multiple methods for array processing have used tightly controlled calibration data sets as the basis for comparison. Here we compare performances for seven processing methods using two data sets originally collected for disease profiling studies. An emphasis is placed on understanding sensitivity for detecting differentially expressed genes in terms of two key statistical determinants: test statistic variability for non-differentially expressed genes, and test statistic size for truly differentially expressed genes. Results In the two data sets considered here, up to seven-fold variation across the processing methods was found in the number of genes detected at a given false discovery rate (FDR). The best performing methods called up to 90% of the same genes differentially expressed, had less variable test statistics under randomization, and had a greater number of large test statistics in the experimental data. Poor performance of one method was directly tied to a tendency to produce highly variable test statistic values under randomization. Based on an overall measure of performance, two of the seven methods (Dchip and a trimmed mean approach) are superior in the two data sets considered here. Two other methods (MAS5 and GCRMA-EB) are inferior, while results for the other three methods are mixed. Conclusions Choice of processing method has a major impact on differential expression analysis of microarray data. Previously reported performance analyses using tightly controlled calibration data sets are not highly consistent with results reported here using data from human tissue samples. Performance of array processing methods in disease profiling and other realistic biological studies should be given greater consideration when comparing Affymetrix processing methods.

Published
2005
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106. Genetic alterations in the adenoma-carcinoma sequence

Author

Cho, Kathleen R. and Vogelstein, Bert

Subjects
Adenoma -- Genetic aspects, Cancer -- Genetic aspects, Carcinogenesis -- Genetic aspects, Health
Abstract

Tumorigenesis is thought to be a multistep process in which genetic alterations accumulate, ultimately producing the neoplastic phenotype. A model was proposed to explain the genetic basis of colorectal neoplasia that included several salient features. First, colorectal tumors appear to occur as a result of the mutational activation of oncogenes coupled with the inactivation of tumor-suppressor genes. Second, mutations in at least four or five genes are required to produce a malignant tumor. Third, although the genetic alterations often occur in a preferred sequence, the total accumulation of changes, rather than their chronologic order of appearance, is responsible for determining the tumor's biologic properties. Several different genetic alterations were identified that occur during colorectal tumorigenesis. Activational

Published
1992

107. Funding anatomic pathology research: a retrospective analysis of an intramural funding mechanism

Author

McDaniel, Andrew, Fullen, Douglas R., Cho, Kathleen R., Lucas, David R., Giordano, Thomas J., Greenson, Joel, Lieberman, Andrew P., Kunju, Lakshmi P., Myers, Jeffrey L., and Roh, Michael H.

Subjects
Research grants -- Reports, Pathology -- Research, Health
Abstract

Context.--In 2006, the department of pathology at our institution established an intramural research funding mechanism to support anatomic pathology research projects for faculty and trainee development. A review committee consisting of faculty members with diverse academic interests evaluated applications; proposals were eligible for a maximum award amount of $30 000 per project with a maximum program cost of $150 000 annually. Objective.--To report our experience based on a retrospective review of the research proposals submitted to the committee since the inception of the Anatomic Pathology Research Fund and evaluate the outcomes of the funded projects. Design.--We retrospectively analyzed all project applications that were received by the committee. Outcome data were collected by reviewing progress reports, abstracts for national and international meetings, PubMed search results, and/or direct communication with investigators. Results.--To date, a total of 59 individual projects have been awarded funding, for a total amount of $349 792, with an average award amount of $5381 per project. A total of 26 faculty members have secured funding for projects through this mechanism, and 27 resident and fellow trainees have been engaged in the funded projects. Spanning 11 subspecialty disciplines in anatomic pathology, 32 abstracts (54%) have been presented at national meetings and 26 (44%) have been published in the peer-reviewed literature to date. One project generated data used to secure an extramural (R01) grant. Conclusions.--Our funding mechanism could serve as a model used by other academic departments to support research activities, thereby fostering faculty development through scholarly activities. (Arch Pathol Lab Med. 2013;137:1270-1273; doi: 10.5858/arpa.2012-0546-OA), Academic pathology represents a unique specialty in medicine owing to the diversity of academic and scholarly activities that can be performed. (1) Research in anatomic pathology represents a proportion of [...]

Published
2013
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109. Uterine Neoplasms, Version 1.2018, NCCN Clinical Practice Guidelines in Oncology

Author

Koh, Wui-Jin, primary, Abu-Rustum, Nadeem R., additional, Bean, Sarah, additional, Bradley, Kristin, additional, Campos, Susana M., additional, Cho, Kathleen R., additional, Chon, Hye Sook, additional, Chu, Christina, additional, Cohn, David, additional, Crispens, Marta Ann, additional, Damast, Shari, additional, Dorigo, Oliver, additional, Eifel, Patricia J., additional, Fisher, Christine M., additional, Frederick, Peter, additional, Gaffney, David K., additional, George, Suzanne, additional, Han, Ernest, additional, Higgins, Susan, additional, Huh, Warner K., additional, Lurain, John R., additional, Mariani, Andrea, additional, Mutch, David, additional, Nagel, Christa, additional, Nekhlyudov, Larissa, additional, Fader, Amanda Nickles, additional, Remmenga, Steven W., additional, Reynolds, R. Kevin, additional, Tillmanns, Todd, additional, Ueda, Stefanie, additional, Wyse, Emily, additional, Yashar, Catheryn M., additional, McMillian, Nicole R., additional, and Scavone, Jillian L., additional

Published
2018
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112. Preclinical Models of Ovarian Cancer: Pathogenesis, Problems, and Implications for Prevention.

Author

Karnezis, Anthony N, Karnezis, Anthony N, Cho, Kathleen R, Karnezis, Anthony N, Karnezis, Anthony N, and Cho, Kathleen R

Abstract

Preclinical models are relatively underutilized and underfunded resources for modeling the pathogenesis and prevention of ovarian cancers. Several reviews have detailed the numerous published models of ovarian cancer. In this review, we will provide an overview of experimental model systems, their strengths and limitations, and use selected models to illustrate how they can be used to address specific issues about ovarian cancer pathogenesis. We will then highlight some of the preclinical prevention studies performed to date and discuss experiments needed to address important unanswered questions about ovarian cancer prevention strategies.

Published
2017

113. Ovarian cancer update: lessons from morphology, molecules, and mice

Author

Cho, Kathleen R.

Subjects
Ovarian cancer -- Diagnosis, Ovarian cancer -- Care and treatment, Ovarian cancer -- Genetic aspects, Morphology -- Analysis, Gene mutations -- Research, Gene mutations -- Physiological aspects, Gene expression -- Research, Gene expression -- Physiological aspects
Abstract

* Ovarian carcinomas are a heterogeneous group of neoplasms. Pathologists currently employ a morphologybased classification system to divide ovarian carcinomas into major subgroups based on degree (tumor grade) and type of differentiation (eg, serous, endometrioid, clear cell, or mucinous). Molecular studies have shown that specific genetic defects are likely to be present in certain histologic types of ovarian carcinomas and unlikely to be present in others. Within the serous and endometrioid carcinomas, the molecular defects in low-grade versus high-grade tumors also appear to be largely distinct. Recently, mouse models of ovarian carcinoma have been developed that recapitulate many of the morphologic features and biologic behavior of selected subtypes of ovarian cancer. It is expected that these mouse models will yield new insights into ovarian cancer pathogenesis and prove useful for preclinical testing of novel strategies for ovarian cancer treatment., When surgical pathologists evaluate an ovarian carcinoma and assign it a particular histopathologic type, grade, and stage, our intent is to convey important information about how that tumor is likely [...]

Published
2009

114. ARID1A-mutated ovarian cancers depend on HDAC6 activity

Author

Bitler, Benjamin G., primary, Wu, Shuai, additional, Park, Pyoung Hwa, additional, Hai, Yang, additional, Aird, Katherine M., additional, Wang, Yemin, additional, Zhai, Yali, additional, Kossenkov, Andrew V., additional, Vara-Ailor, Ana, additional, Rauscher III, Frank J., additional, Zou, Weiping, additional, Speicher, David W., additional, Huntsman, David G., additional, Conejo-Garcia, Jose R., additional, Cho, Kathleen R., additional, Christianson, David W., additional, and Zhang, Rugang, additional

Published
2017
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117. BRAFV600E cooperates with CDX2 inactivation to promote serrated colorectal tumorigenesis

Author

Sakamoto, Naoya, primary, Feng, Ying, additional, Stolfi, Carmine, additional, Kurosu, Yuki, additional, Green, Maranne, additional, Lin, Jeffry, additional, Green, Megan E, additional, Sentani, Kazuhiro, additional, Yasui, Wataru, additional, McMahon, Martin, additional, Hardiman, Karin M, additional, Spence, Jason R, additional, Horita, Nobukatsu, additional, Greenson, Joel K, additional, Kuick, Rork, additional, Cho, Kathleen R, additional, and Fearon, Eric R, additional

Published
2017
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119. Vulvar Cancer, Version 1.2017, NCCN Clinical Practice Guidelines in Oncology

Author

Koh, Wui-Jin, primary, Greer, Benjamin E., additional, Abu-Rustum, Nadeem R., additional, Campos, Susana M., additional, Cho, Kathleen R., additional, Chon, Hye Sook, additional, Chu, Christina, additional, Cohn, David, additional, Crispens, Marta Ann, additional, Dizon, Don S., additional, Dorigo, Oliver, additional, Eifel, Patricia J., additional, Fisher, Christine M., additional, Frederick, Peter, additional, Gaffney, David K., additional, Han, Ernest, additional, Higgins, Susan, additional, Huh, Warner K., additional, Lurain, John R., additional, Mariani, Andrea, additional, Mutch, David, additional, Nagel, Christa, additional, Nekhlyudov, Larissa, additional, Fader, Amanda Nickles, additional, Remmenga, Steven W., additional, Reynolds, R. Kevin, additional, Tillmanns, Todd, additional, Ueda, Stefanie, additional, Valea, Fidel A., additional, Wyse, Emily, additional, Yashar, Catheryn M., additional, McMillian, Nicole, additional, and Scavone, Jillian, additional

Published
2016
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120. Author response: BRAFV600E cooperates with CDX2 inactivation to promote serrated colorectal tumorigenesis

Author

Sakamoto, Naoya, primary, Feng, Ying, additional, Stolfi, Carmine, additional, Kurosu, Yuki, additional, Green, Maranne, additional, Lin, Jeffry, additional, Green, Megan E, additional, Sentani, Kazuhiro, additional, Yasui, Wataru, additional, McMahon, Martin, additional, Hardiman, Karin M, additional, Spence, Jason R, additional, Horita, Nobukatsu, additional, Greenson, Joel K, additional, Kuick, Rork, additional, Cho, Kathleen R, additional, and Fearon, Eric R, additional

Published
2016
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125. Genomic Profiling of Penile Squamous Cell Carcinoma Reveals New Opportunities for Targeted Therapy

Author

McDaniel, Andrew S., primary, Hovelson, Daniel H., additional, Cani, Andi K., additional, Liu, Chia-Jen, additional, Zhai, Yali, additional, Zhang, Yajia, additional, Weizer, Alon Z., additional, Mehra, Rohit, additional, Feng, Felix Y., additional, Alva, Ajjai S., additional, Morgan, Todd M., additional, Montgomery, Jeffrey S., additional, Siddiqui, Javed, additional, Sadis, Seth, additional, Bandla, Santhoshi, additional, Williams, Paul D., additional, Cho, Kathleen R., additional, Rhodes, Daniel R., additional, and Tomlins, Scott A., additional

Published
2015
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126. Tissue-Specific Effects of Reduced β-catenin Expression on Adenomatous Polyposis Coli Mutation-Instigated Tumorigenesis in Mouse Colon and Ovarian Epithelium

Author

Feng, Ying, primary, Sakamoto, Naoya, additional, Wu, Rong, additional, Liu, Jie-yu, additional, Wiese, Alexandra, additional, Green, Maranne E., additional, Green, Megan, additional, Akyol, Aytekin, additional, Roy, Badal C., additional, Zhai, Yali, additional, Cho, Kathleen R., additional, and Fearon, Eric R., additional

Published
2015
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127. Uterine Sarcoma, Version 1.2016

Author

Koh, Wui-Jin, primary, Greer, Benjamin E., additional, Abu-Rustum, Nadeem R., additional, Apte, Sachin M., additional, Campos, Susana M., additional, Cho, Kathleen R., additional, Chu, Christina, additional, Cohn, David, additional, Crispens, Marta Ann, additional, Dizon, Don S., additional, Dorigo, Oliver, additional, Eifel, Patricia J., additional, Fisher, Christine M., additional, Frederick, Peter, additional, Gaffney, David K., additional, George, Suzanne, additional, Han, Ernest, additional, Higgins, Susan, additional, Huh, Warner K., additional, Lurain, John R., additional, Mariani, Andrea, additional, Mutch, David, additional, Fader, Amanda Nickles, additional, Remmenga, Steven W., additional, Reynolds, R. Kevin, additional, Tillmanns, Todd, additional, Valea, Fidel A., additional, Yashar, Catheryn M., additional, McMillian, Nicole R., additional, and Scavone, Jillian L., additional

Published
2015
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128. IS "OVARIAN" CANCER A MISNOMER? EXPLORING OVARIAN CANCER ORIGINS IN THE MOUSE.

Author

CHO, KATHLEEN R.

Subjects
OVARIAN cancer prevention, EPITHELIUM, FALLOPIAN tube diseases, NEOPLASTIC cell transformation, MORPHOLOGY
Abstract

Ovarian cancer is a generic term that encompasses several different tumor types. The most common and lethal type is known as high-grade serous carcinoma. The cellular origin of high-grade serous carcinoma has been debated for many years, but recent studies suggest that many, if not most, arise from epithelium in the fallopian tube rather than from the ovarian surface epithelium. Genetically engineered mice have been used to study the consequences of transforming epithelium in the oviduct (mouse fallopian tube equivalent) versus the ovarian surface epithelium, and to test whether genetic alterations characteristic of specific types of human ovarian cancers will lead to morphologically and biologically similar tumors in the mouse. Recent studies show that the mouse tumor phenotype is highly dependent on both cell of origin and the specific genetic alterations underlying neoplastic transformation, with mouse tumors based on transformation of oviductal epithelium more closely recapitulating their human tumor counterparts than those based on ovarian surface epithelium transformation. Understanding the cellular origins of ovarian cancer has significant implications for improving ovarian cancer prevention and early detection. [ABSTRACT FROM AUTHOR]

Published
2018

129. Trp53null and R270H mutant alleles have comparable effects in regulating invasion, metastasis, and gene expression in mouse colon tumorigenesis

Author

Tang, Jinyu, Feng, Ying, Kuick, Rork, Green, Megan, Green, Maranne, Sakamoto, Naoya, Kurosu, Yuki, Lin, Jeffry, Cho, Kathleen R., and Fearon, Eric R.

Abstract

Somatic APC(adenomatous polyposis coli), TP53, KRASmutations are present in roughly 80%, 60%, and 40%, respectively, of human colorectal cancers (CRCs). Most TP53mutant alleles in CRCs encode missense mutant proteins with loss-of-function (LOF) of p53’s transcriptional activity and dominant negative (DN) effects on wild-type p53 function. Missense mutant p53 proteins have been reported to exert gain-of-function (GOF) effects in cancer. We compared the phenotypic effects of the common human cancer-associated TP53R273H missense mutation to p53 null status in a genetically engineered mouse CRC model. Inactivation of one allele of Apctogether with activation of a Krasmutant allele in mouse colon epithelium instigated development of serrated and hyperplastic epithelium and adenomas (AK mice). Addition of a Trp53R270Hor Trp53nullmutant allele to the model (AKP mice) led to markedly shortened survival and increased tumor burden relative to that of AK mice, including adenocarcinomas in AKP mice. Comparable life span and tumor burden were seen in AKP mice carrying Trp53R270Hor Trp53nullalleles, along with similar frequencies of spontaneous metastasis to lymph nodes, lung, and liver. The fraction of adenocarcinomas with submucosa or deeper invasion was higher in AKP270/flmice than in AKPfl/flmice, but the incidence of adenocarcinomas per mouse did not differ significantly between AKPfl/fland AKP270/flmice. In line with their comparable biological behaviors, mouse primary tumors and tumor-derived organoids with the Trp53R270Hor Trp53nullalleles had highly similar gene expression profiles. Human CRCs with TP53R273 missense mutant or null alleles also had essentially homogeneous gene expression patterns. Our findings indicate the R270H/R273H p53 mutant protein does not manifest definite GOF biological effects in mouse and human CRCs, suggesting possible GOF effects of mutant p53 in cancer phenotypes are likely allele-specific and/or context-dependent.

Published
2019
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134. Cervical Cancer, Version 2.2015

Author

Koh, Wui-Jin, primary, Greer, Benjamin E., additional, Abu-Rustum, Nadeem R., additional, Apte, Sachin M., additional, Campos, Susana M., additional, Cho, Kathleen R., additional, Chu, Christina, additional, Cohn, David, additional, Crispens, Marta Ann, additional, Dorigo, Oliver, additional, Eifel, Patricia J., additional, Fisher, Christine M., additional, Frederick, Peter, additional, Gaffney, David K., additional, Han, Ernest, additional, Huh, Warner K., additional, Lurain, John R., additional, Mutch, David, additional, Fader, Amanda Nickles, additional, Remmenga, Steven W., additional, Reynolds, R. Kevin, additional, Teng, Nelson, additional, Tillmanns, Todd, additional, Valea, Fidel A., additional, Yashar, Catheryn M., additional, McMillian, Nicole R., additional, and Scavone, Jillian L., additional

Published
2015
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137. Impact of oviductal versus ovarian epithelial cell of origin on ovarian endometrioid carcinoma phenotype in the mouse.

Author

Wu, Rong, Zhai, Yali, Kuick, Rork, Karnezis, Anthony N, Garcia, Paloma, Naseem, Anum, Hu, Tom C, Fearon, Eric R, and Cho, Kathleen R

Abstract

Endometrioid carcinoma ( EC) is a relatively indolent ovarian carcinoma subtype that is nonetheless deadly if detected late. Existing genetically engineered mouse models ( GEMMs) of the disease, based on transformation of the ovarian surface epithelium ( OSE), take advantage of known ovarian EC driver gene lesions, but do not fully recapitulate the disease features seen in patients. An EC model in which the Apc and Pten tumour suppressor genes are conditionally deleted in murine OSE yields tumours that are biologically more aggressive and significantly less differentiated than human ECs. Importantly, OSE is not currently thought to be the tissue of origin of most ovarian cancers, including ECs, suggesting that tumour initiation in Müllerian epithelium may produce tumours that more closely resemble their human tumour counterparts. We have developed Ovgp1- iCreERT2 mice in which the Ovgp1 promoter controls expression of tamoxifen ( TAM)-regulated Cre recombinase in oviductal epithelium - the murine equivalent of human Fallopian tube epithelium. Ovgp1- iCreERT2;Apcfl/fl;Ptenfl/fl mice treated with TAM or injected with adenovirus expressing Cre into the ovarian bursa uniformly develop oviductal or ovarian ECs, respectively. On the basis of their morphology and global gene expression profiles, the oviduct-derived tumours more closely resemble human ovarian ECs than do OSE-derived tumours. Furthermore, mice with oviductal tumours survive much longer than their counterparts with ovarian tumours. The slow progression and late metastasis of oviductal tumours resembles the relatively indolent behaviour characteristic of so-called Type I ovarian carcinomas in humans, for which EC is a prototype. Our studies demonstrate the utility of Ovgp1- iCreERT2 mice for manipulating genes of interest specifically in the oviductal epithelium, and establish that the cell of origin is an important consideration in mouse ovarian cancer GEMMs. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Published
2016
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138. Comparison of seven methods for producing Affymetrix expression scores based on False Discovery Rates in disease profiling data

Author

Gruber Stephen B, Giordano Thomas J, Cho Kathleen R, Macdonald James, Ghosh Debashis, Kuick Rork, Chen Wei, Shedden Kerby, Fearon Eric R, Taylor Jeremy MG, and Hanash Samir

Subjects
Transcription, Genetic, Gene Expression, lcsh:Computer applications to medicine. Medical informatics, Models, Biological, Sensitivity and Specificity, Random Allocation, Humans, Computer Simulation, False Positive Reactions, lcsh:QH301-705.5, Oligonucleotide Array Sequence Analysis, Analysis of Variance, Models, Statistical, Models, Genetic, Gene Expression Profiling, Computational Biology, Reproducibility of Results, Sequence Analysis, DNA, lcsh:Biology (General), Research Design, Data Interpretation, Statistical, Calibration, lcsh:R858-859.7, RNA, DNA Probes, Oligonucleotide Probes, Algorithms, Software, Research Article
Abstract

Background A critical step in processing oligonucleotide microarray data is combining the information in multiple probes to produce a single number that best captures the expression level of a RNA transcript. Several systematic studies comparing multiple methods for array processing have used tightly controlled calibration data sets as the basis for comparison. Here we compare performances for seven processing methods using two data sets originally collected for disease profiling studies. An emphasis is placed on understanding sensitivity for detecting differentially expressed genes in terms of two key statistical determinants: test statistic variability for non-differentially expressed genes, and test statistic size for truly differentially expressed genes. Results In the two data sets considered here, up to seven-fold variation across the processing methods was found in the number of genes detected at a given false discovery rate (FDR). The best performing methods called up to 90% of the same genes differentially expressed, had less variable test statistics under randomization, and had a greater number of large test statistics in the experimental data. Poor performance of one method was directly tied to a tendency to produce highly variable test statistic values under randomization. Based on an overall measure of performance, two of the seven methods (Dchip and a trimmed mean approach) are superior in the two data sets considered here. Two other methods (MAS5 and GCRMA-EB) are inferior, while results for the other three methods are mixed. Conclusions Choice of processing method has a major impact on differential expression analysis of microarray data. Previously reported performance analyses using tightly controlled calibration data sets are not highly consistent with results reported here using data from human tissue samples. Performance of array processing methods in disease profiling and other realistic biological studies should be given greater consideration when comparing Affymetrix processing methods.

Published
2004

139. Uterine Neoplasms, Version 1.2014

Author

Koh, Wui-Jin, primary, Greer, Benjamin E., additional, Abu-Rustum, Nadeem R., additional, Apte, Sachin M., additional, Campos, Susana M., additional, Chan, John, additional, Cho, Kathleen R., additional, Cohn, David, additional, Crispens, Marta Ann, additional, DuPont, Nefertiti, additional, Eifel, Patricia J., additional, Fader, Amanda Nickles, additional, Fisher, Christine M., additional, Gaffney, David K., additional, George, Suzanne, additional, Han, Ernest, additional, Huh, Warner K., additional, Lurain, John R., additional, Martin, Lainie, additional, Mutch, David, additional, Remmenga, Steven W., additional, Reynolds, R. Kevin, additional, Small, William, additional, Teng, Nelson, additional, Tillmanns, Todd, additional, Valea, Fidel A., additional, McMillian, Nicole, additional, and Hughes, Miranda, additional

Published
2014
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140. Development of Mouse Models of Ovarian Cancer for Studying Tumor Biology and Testing Novel Molecularly Targeted Therapeutic Strategies

Author

MICHIGAN UNIV ANN ARBOR, Cho, Kathleen R, Rehemtulla, Alnawaz, MICHIGAN UNIV ANN ARBOR, Cho, Kathleen R, and Rehemtulla, Alnawaz

Abstract

The objective of this project was to create genetically engineered mouse (GEM) models that in addition to developing ovarian carcinomas similar to human endometrioid carcinomas, also express a reporter for Caspase-3 activity, a hallmark of cells undergoing apoptosis. During the three year funding period, we generated stable lines of transgenic mice carrying a Cre-inducible luciferase reporter (ROSA26LSL-Luc) or apoptosis reporter (ApoptosisLSL-Luc) and verified function of the reporter transgenes in vivo. Using Apcflox/flox;Ptenflox/flox;ROSA26LSL-Luc/+ and Apcflox/flox;Ptenflox/flox;ApoptosisLSL-Luc mice generated as part of this project, we demonstrated that bioluminescence imaging can be used to monitor ovarian tumor progression and drug response in vivo. In addition, we showed that Apcflox/flox;Ptenflox/flox;ApoptosisLSL-Luc mice can be used to image treatment-dependent induction of apoptosis. Efficacy of a targeted therapeutic agent (Akt inhibitor, Perifosine), alone and in combination with a standard chemotherapeutic agent (Cisplatin) was evaluated. Our studies revealed that combination therapy resulted in enhanced levels of apoptosis compared to either agent alone, and suggest this may be a promising approach for treating women with advanced stage ovarian endometrioid adenocarcinomas with PI3K/Akt/mTOR signaling pathway defects.

Published
2011

141. Mutant KRAS promotes hyperplasia and alters differentiation in the colon epithelium but does not expand the presumptive stem cell pool.

Author

UCL - SSS/DDUV - Institut de Duve, autre - University of Michigan, Feng, Ying, Bommer, Guido, Zhao, Jenny, Green, Maranne, Sands, Evan, Zhai, Yali, Brown, Kelly, Burberry, Aaron, Cho, Kathleen R, Fearon, Eric R, UCL - SSS/DDUV - Institut de Duve, autre - University of Michigan, Feng, Ying, Bommer, Guido, Zhao, Jenny, Green, Maranne, Sands, Evan, Zhai, Yali, Brown, Kelly, Burberry, Aaron, Cho, Kathleen R, and Fearon, Eric R

Abstract

Although Kras/KRAS mutation promotes serrated and hyperplastic morphologic features in colon epithelium, it is not able to initiate adenoma development, perhaps in part because activated Kras/KRAS signaling does not increase the number of presumptive stem cells in affected crypts.

Published
2011

142. Loss of estrogen receptor 1 enhances cervical cancer invasion.

Author

UCL - SSS/DDUV - Institut de Duve, autre - University of Michigan, Zhai, Yali, Bommer, Guido, Feng, Ying, Wiese, Alexandra B, Fearon, Eric R, Cho, Kathleen R, UCL - SSS/DDUV - Institut de Duve, autre - University of Michigan, Zhai, Yali, Bommer, Guido, Feng, Ying, Wiese, Alexandra B, Fearon, Eric R, and Cho, Kathleen R

Abstract

If left untreated, some cervical high-grade squamous intraepithelial lesions will progress to invasive squamous cell carcinoma (SCC), but the molecular events conferring invasive potential remain poorly defined. In prior work, we identified 48 genes that were down-regulated in SCCs compared with high-grade squamous intraepithelial lesions and normal squamous epithelia. In this study, a functional screening strategy was used to identify which of these genes regulate cervical cancer cell invasion. Two independent squamous epithelial cell lines were transduced with a library of short hairpin RNAs targeting the differentially expressed genes and tested for invasion of the chick chorioallantoic membrane. PCR was used to recover specific short hairpin RNAs from cells that invaded the chorioallantoic membrane. Constructs targeting estrogen receptor 1 (ESR1) were highly enriched in the invasive cells. The short hairpin RNA-mediated inhibition of ESR1 in SCC- and precancer-derived cell lines increased invasiveness in both in vivo and in vitro assays. Conversely, restoration of ESR1 expression in ESR1-negative cervical cancer cells reduced cell invasiveness. Loss of ESR1 expression was found to accompany cervical cancer progression in an analysis of primary normal cervix, low grade squamous intraepithelial lesions, high-grade squamous intraepithelial lesions, and SCC specimens. Molecular mechanisms underlying down-regulation of ESR1 in invasive cervical carcinomas appear to be complex and likely heterogeneous. Our findings indicate that loss of ESR1 has a major role in mediating cervical cancer invasion and progression.

Published
2010

143. IRS1 regulation by Wnt/beta-catenin signaling and varied contribution of IRS1 to the neoplastic phenotype.

Author

UCL - SSS/DDUV - Institut de Duve, Bommer, Guido, Feng, Ying, Iura, Ayaka, Giordano, Thomas J, Kuick, Rork, Kadikoy, Hüseyin, Sikorski, Deanna, Wu, Rong, Cho, Kathleen R, Fearon, Eric R, UCL - SSS/DDUV - Institut de Duve, Bommer, Guido, Feng, Ying, Iura, Ayaka, Giordano, Thomas J, Kuick, Rork, Kadikoy, Hüseyin, Sikorski, Deanna, Wu, Rong, Cho, Kathleen R, and Fearon, Eric R

Abstract

Dysregulation of beta-catenin levels and localization and constitutive activation of beta-catenin/TCF (T cell factor)-regulated gene expression occur in many cancers, including the majority of colorectal carcinomas and a subset of ovarian endometrioid adenocarcinomas. Based on the results of microarray-based gene expression profiling we found the insulin receptor substrate 1 (IRS1) gene as one of the most highly up-regulated genes upon ectopic expression of a mutant, constitutively active form of beta-catenin in the rat kidney epithelial cell line RK3E. We demonstrate expression of IRS1 can be directly activated by beta-catenin, likely in part via beta-catenin/TCF binding to TCF consensus binding elements located in the first intron and downstream of the IRS1 transcriptional start site. Consistent with the proposal that beta-catenin is an important regulator of IRS1 expression in vivo, we observed that IRS1 is highly expressed in many cancers with constitutive stabilization of beta-catenin, such as colorectal carcinomas and ovarian endometrioid adenocarcinomas. Using a short hairpin RNA approach to abrogate IRS1 expression and function, we found that IRS1 function is required for efficient de novo neoplastic transformation by beta-catenin in RK3E cells. Our findings add to the growing body of data implicating IRS1 as a critical signaling component in cancer development and progression.

Published
2010

144. IRS1 regulation by wnt/beta-catenin signaling and varied contribution of IRS1 to the neoplastic phenotype

Author

UCL - MD/BICL - Département de biochimie et de biologie cellulaire, Bommer, Guido, Feng, Ying, Iura, Ayaka, Giordano, Thomas J, Kuick, Rork, Kadikoy, Huseyin, Sikorski, Deanna, Wu, Rong, Cho, Kathleen R, Fearon, Eric R, UCL - MD/BICL - Département de biochimie et de biologie cellulaire, Bommer, Guido, Feng, Ying, Iura, Ayaka, Giordano, Thomas J, Kuick, Rork, Kadikoy, Huseyin, Sikorski, Deanna, Wu, Rong, Cho, Kathleen R, and Fearon, Eric R

Abstract

Dysregulation of beta-catenin levels and localization and constitutive activation of beta-catenin/TCF (T cell factor)-regulated gene expression occurs in many cancers, including the majority of colorectal carcinomas (CRCs) and a subset of ovarian endometrioid adenocarcinomas (OEAs). Based on the results of microarray-based gene expression profiling we found the insulin receptor substrate 1 (IRS1) gene as one of the most highly upregulated genes upon ectopic expression of a mutant, constitutively active form of beta-catenin in the rat kidney epithelial cell line RK3E. We demonstrate that expression of IRS1 can be directly activated by beta-catenin, likely in part via beta-catenin/TCF binding to TCF consensus binding elements located in the first intron and downstream of the IRS1 transcriptional start site. Consistent with the proposal that beta-catenin is an important regulator of IRS1 expression in vivo, we observed that IRS1 is highly expressed in many cancers with constitutive stabilization of beta-catenin, such as CRCs and OEAs. Using an shRNA approach to abrogate IRS1 expression and function, we found IRS1 function is required for efficient de novo neoplastic transformation by beta-catenin in RK3E cells. Our findings add to the growing body of data implicating IRS1 as a critical signaling component in cancer development and progression.

Published
2009

146. Two Distinct Categories of Focal Deletions in Cancer Genomes

Author

Rajaram, Megha, primary, Zhang, Jianping, additional, Wang, Tim, additional, Li, Jinyu, additional, Kuscu, Cem, additional, Qi, Huan, additional, Kato, Mamoru, additional, Grubor, Vladimir, additional, Weil, Robert J., additional, Helland, Aslaug, additional, Borrenson-Dale, Anne-Lise, additional, Cho, Kathleen R., additional, Levine, Douglas A., additional, Houghton, Alan N., additional, Wolchok, Jedd D., additional, Myeroff, Lois, additional, Markowitz, Sanford D., additional, Lowe, Scott W., additional, Zhang, Michael, additional, Krasnitz, Alex, additional, Lucito, Robert, additional, Mu, David, additional, and Powers, R. Scott, additional

Published
2013
Full Text
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147. Cervical Cancer

Author

Koh, Wui-Jin, primary, Greer, Benjamin E., additional, Abu-Rustum, Nadeem R., additional, Apte, Sachin M., additional, Campos, Susana M., additional, Chan, John, additional, Cho, Kathleen R., additional, Cohn, David, additional, Crispens, Marta Ann, additional, DuPont, Nefertiti, additional, Eifel, Patricia J., additional, Gaffney, David K., additional, Giuntoli, Robert L., additional, Han, Ernest, additional, Huh, Warner K., additional, Lurain, John R., additional, Martin, Lainie, additional, Morgan, Mark A., additional, Mutch, David, additional, Remmenga, Steven W., additional, Reynolds, R. Kevin, additional, Small, William, additional, Teng, Nelson, additional, Tillmanns, Todd, additional, Valea, Fidel A., additional, McMillian, Nicole R., additional, and Hughes, Miranda, additional

Published
2013
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149. p53-mediated activation of miRNA34 candidate tumor-suppressor genes.

Author

University of Michigan - Internal Medicine, UCL - Autre, Bommer, Guido, Gerin, Isabelle, Feng, Ying, Kaczorowski, Andrew J, Kuick, Rork, Love, Robert E, Zhai, Yali, Giordano, Thomas J, Qin, Zhaohui S, Moore, Bethany B, MacDougald, Ormond A, Cho, Kathleen R, Fearon, Eric R, University of Michigan - Internal Medicine, UCL - Autre, Bommer, Guido, Gerin, Isabelle, Feng, Ying, Kaczorowski, Andrew J, Kuick, Rork, Love, Robert E, Zhai, Yali, Giordano, Thomas J, Qin, Zhaohui S, Moore, Bethany B, MacDougald, Ormond A, Cho, Kathleen R, and Fearon, Eric R

Abstract

Taken together, the data suggest the miRNA34s might be key effectors of p53 tumor-suppressor function, and their inactivation might contribute to certain cancers.

Published
2007

150. Drosophila split ends homologue SHARP functions as a positive regulator of Wnt/beta-catenin/T-cell factor signaling in neoplastic transformation.

Author

autre - University of Michigan, UCL - Autre, Feng, Ying, Bommer, Guido, Zhai, Yali, Akyol, Aytekin, Hinoi, Takao, Winer, Ira, Lin, Hua V, Cadigan, Ken M, Cho, Kathleen R, Fearon, Eric R, autre - University of Michigan, UCL - Autre, Feng, Ying, Bommer, Guido, Zhai, Yali, Akyol, Aytekin, Hinoi, Takao, Winer, Ira, Lin, Hua V, Cadigan, Ken M, Cho, Kathleen R, and Fearon, Eric R

Abstract

Wnt ligands have pleiotropic and context-specific roles in embryogenesis and adult tissues. Among other effects, certain Wnts stabilize the beta-catenin protein, leading to the ability of beta-catenin to activate T-cell factor (TCF)-mediated transcription. Mutations resulting in constitutive beta-catenin stabilization underlie development of several human cancers. Genetic studies in Drosophila highlighted the split ends (spen) gene as a positive regulator of Wnt-dependent signaling. We have assessed the role of SHARP, a human homologue of spen, in Wnt/beta-catenin/TCF function in mammalian cells. We found that SHARP gene and protein expression is elevated in human colon and ovarian endometrioid adenocarcinomas and mouse colon adenomas and carcinomas carrying gene defects leading to beta-catenin dysregulation. When ectopically expressed, the silencing mediator for retinoid and thyroid receptors/histone deacetylase 1-associated repressor protein (SHARP) protein potently enhanced beta-catenin/TCF transcription of a model reporter gene and cellular target genes. Inhibition of endogenous SHARP function via RNA inhibitory (RNAi) approaches antagonized beta-catenin/TCF-mediated activation of target genes. The effect of SHARP on beta-catenin/TCF-regulated genes was mediated via a functional interaction between SHARP and TCF. beta-Catenin-dependent neoplastic transformation of RK3E cells was enhanced by ectopic expression of SHARP, and RNAi-mediated inhibition of endogenous SHARP in colon cancer cells inhibited their transformed growth. In toto, our findings implicate SHARP as an important positive regulator of Wnt signaling in cancers with beta-catenin dysregulation.

Published
2007

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