Progesterone Receptor-A Isoform Interaction with RUNX Transcription Factors Controls
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RUNX1 Control of Mammary Epithelial and Breast Cancer Cell Phenotypes
University of Massachusetts Medical School eScholarship@UMMS GSBS Dissertations and Theses Graduate School of Biomedical Sciences 2017-12-12 RUNX1 Control of Mammary Epithelial and Breast Cancer Cell Phenotypes Deli Hong University of Massachusetts Medical School Let us know how access to this document benefits ou.y Follow this and additional works at: https://escholarship.umassmed.edu/gsbs_diss Part of the Cancer Biology Commons, and the Cell Biology Commons Repository Citation Hong D. (2017). RUNX1 Control of Mammary Epithelial and Breast Cancer Cell Phenotypes. GSBS Dissertations and Theses. https://doi.org/10.13028/M21Q2F. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/949 This material is brought to you by eScholarship@UMMS. It has been accepted for inclusion in GSBS Dissertations and Theses by an authorized administrator of eScholarship@UMMS. For more information, please contact [email protected]. RUNX1 CONTROL OF MAMMARY EPITHELIAL AND BREAST CANCER CELL PHENOTYPES A Dissertation Presented By Deli Hong Submitted to the Faculty of the University of Massachusetts Graduate School of Biomedical Sciences, Worcester in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY December 12, 2017 Program of Cell Biology RUNX1 CONTROL OF MAMMARY EPITHELIAL AND BREAST CANCER CELL PHENOTYPES A Dissertation Presented By Deli Hong This work was undertaken in the Graduate School of Biomedical Sciences Program of Cell Biology The signature of the Thesis Advisor signifies validation of Dissertation content Gary S. Stein, Ph. D., Thesis Advisor The signatures of the Dissertation Defense Committee signify completion and approval as to style and content of the Dissertation Leslie Shaw, Ph. -
Functions of the Mineralocorticoid Receptor in the Hippocampus By
Functions of the Mineralocorticoid Receptor in the Hippocampus by Aaron M. Rozeboom A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Cellular and Molecular Biology) in The University of Michigan 2008 Doctoral Committee: Professor Audrey F. Seasholtz, Chair Professor Elizabeth A. Young Professor Ronald Jay Koenig Associate Professor Gary D. Hammer Assistant Professor Jorge A. Iniguez-Lluhi Acknowledgements There are more people than I can possibly name here that I need to thank who have helped me throughout the process of writing this thesis. The first and foremost person on this list is my mentor, Audrey Seasholtz. Between working in her laboratory as a research assistant and continuing my training as a graduate student, I spent 9 years in Audrey’s laboratory and it would be no exaggeration to say that almost everything I have learned regarding scientific research has come from her. Audrey’s boundless enthusiasm, great patience, and eager desire to teach students has made my time in her laboratory a richly rewarding experience. I cannot speak of Audrey’s laboratory without also including all the past and present members, many of whom were/are not just lab-mates but also good friends. I also need to thank all the members of my committee, an amazing group of people whose scientific prowess combined with their open-mindedness allowed me to explore a wide variety of interests while maintaining intense scientific rigor. Outside of Audrey’s laboratory, there have been many people in Ann Arbor without whom I would most assuredly have gone crazy. -
GATA3 As an Adjunct Prognostic Factor in Breast Cancer Patients with Less Aggressive Disease: a Study with a Review of the Literature
diagnostics Article GATA3 as an Adjunct Prognostic Factor in Breast Cancer Patients with Less Aggressive Disease: A Study with a Review of the Literature Patrizia Querzoli 1, Massimo Pedriali 1 , Rosa Rinaldi 2 , Paola Secchiero 3, Paolo Giorgi Rossi 4 and Elisabetta Kuhn 5,6,* 1 Section of Anatomic Pathology, Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, 44124 Ferrara, Italy; [email protected] (P.Q.); [email protected] (M.P.) 2 Section of Anatomic Pathology, ASST Mantova, Ospedale Carlo Poma, 46100 Mantova, Italy; [email protected] 3 Surgery and Experimental Medicine and Interdepartmental Center of Technology of Advanced Therapies (LTTA), Department of Morphology, University of Ferrara, 44121 Ferrara, Italy; [email protected] 4 Epidemiology Unit, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy; [email protected] 5 Division of Pathology, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, 20122 Milano, Italy 6 Department of Biomedical, Surgical, and Dental Sciences, University of Milan, 20122 Milano, Italy * Correspondence: [email protected]; Tel.: +39-02-5032-0564; Fax: +39-02-5503-2860 Abstract: Background: GATA binding protein 3 (GATA3) expression is positively correlated with Citation: Querzoli, P.; Pedriali, M.; estrogen receptor (ER) expression, but its prognostic value as an independent factor remains unclear. Rinaldi, R.; Secchiero, P.; Rossi, P.G.; Thus, we undertook the current study to evaluate the expression of GATA3 and its prognostic value Kuhn, E. GATA3 as an Adjunct in a large series of breast carcinomas (BCs) with long-term follow-up. Methods: A total of 702 Prognostic Factor in Breast Cancer consecutive primary invasive BCs resected between 1989 and 1993 in our institution were arranged Patients with Less Aggressive in tissue microarrays, immunostained for ER, progesterone receptor (PR), ki-67, HER2, p53, and Disease: A Study with a Review of GATA3, and scored. -
Progesterone Receptor Isoform B Regulates the Oxtr-Plcl2-Trpc3 Pathway to Suppress Uterine Contractility
Progesterone receptor isoform B regulates the Oxtr-Plcl2-Trpc3 pathway to suppress uterine contractility Mary C. Peaveya,1, San-Pin Wub,1, Rong Lib, Jian Liub, Olivia M. Emeryb, Tianyuan Wangc, Lecong Zhouc, Margeaux Wetendorfd, Chandra Yallampallie, William E. Gibbonse, John P. Lydond, and Francesco J. DeMayob,2 aDepartment of Obstetrics and Gynecology, University of North Carolina, Chapel Hill, NC 27599; bReproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709; cIntegrative Bioinformatic Support Group, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709; dDepartment of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030; and eDepartment of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX 77030 Edited by R. Michael Roberts, University of Missouri, Columbia, MO, and approved January 19, 2021 (received for review June 6, 2020) Uterine contractile dysfunction leads to pregnancy complications The “progesterone receptor isoform switch” concept was posited such as preterm birth and labor dystocia. In humans, it is hypoth- to explain the transition from a quiescent to a contractile myometrial esized that progesterone receptor isoform PGR-B promotes a re- phenotype in the presence of high levels of progesterone (10, 11, laxed state of the myometrium, and PGR-A facilitates uterine 26–30). Progesterone acts via the nuclear receptor isoforms, PGR-A contraction. This hypothesis was tested in vivo using transgenic and PGR-B, which are coexpressed at different levels throughout mouse models that overexpress PGR-A or PGR-B in smooth muscle pregnancy (31–35). Progesterone can transactivate different tran- cells. Elevated PGR-B abundance results in a marked increase in scriptional programs determined by the relative levels of PGR-A and gestational length compared to control mice (21.1 versus 19.1 d PGR-B isoforms in the myometrium (36–41). -
The Novel Progesterone Receptor
0013-7227/99/$03.00/0 Vol. 140, No. 3 Endocrinology Printed in U.S.A. Copyright © 1999 by The Endocrine Society The Novel Progesterone Receptor Antagonists RTI 3021– 012 and RTI 3021–022 Exhibit Complex Glucocorticoid Receptor Antagonist Activities: Implications for the Development of Dissociated Antiprogestins* B. L. WAGNER†, G. POLLIO, P. GIANGRANDE‡, J. C. WEBSTER, M. BRESLIN, D. E. MAIS, C. E. COOK, W. V. VEDECKIS, J. A. CIDLOWSKI, AND D. P. MCDONNELL Department of Pharmacology and Cancer Biology (B.L.W., G.P., P.G., D.P.M.), Duke University Medical Center, Durham, North Carolina 27710; Molecular Endocrinology Group (J.C.W., J.A.C.), NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709; Department of Biochemistry and Molecular Biology (M.B., W.V.V.), Louisiana State University Medical School, New Orleans, Louisiana 70112; Ligand Pharmaceuticals, Inc. (D.E.M.), San Diego, California 92121; Research Triangle Institute (C.E.C.), Chemistry and Life Sciences, Research Triangle Park, North Carolina 27709 ABSTRACT by agonists for DNA response elements within target gene promoters. We have identified two novel compounds (RTI 3021–012 and RTI Accordingly, we observed that RU486, RTI 3021–012, and RTI 3021– 3021–022) that demonstrate similar affinities for human progeste- 022, when assayed for PR antagonist activity, accomplished both of rone receptor (PR) and display equivalent antiprogestenic activity. As these steps. Thus, all three compounds are “active antagonists” of PR with most antiprogestins, such as RU486, RTI 3021–012, and RTI function. When assayed on GR, however, RU486 alone functioned as 3021–022 also bind to the glucocorticoid receptor (GR) with high an active antagonist. -
And EZH2-Regulated Gene, Has Differential Roles in AR-Dependent and -Independent Prostate Cancer
www.impactjournals.com/oncotarget/ Oncotarget, Vol. 6, No.4 RUNX1, an androgen- and EZH2-regulated gene, has differential roles in AR-dependent and -independent prostate cancer Ken-ichi Takayama1,2, Takashi Suzuki3, Shuichi Tsutsumi4, Tetsuya Fujimura5, Tomohiko Urano1,2, Satoru Takahashi6, Yukio Homma5, Hiroyuki Aburatani4 and Satoshi Inoue1,2,7 1 Department of Anti-Aging Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan 2 Department of Geriatric Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan 3 Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan 4 Genome Science Division, Research Center for Advanced Science and Technology (RCAST), The University of Tokyo, Meguro-ku, Tokyo, Japan 5 Department of Urology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan 6 Department of Urology, Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan 7 Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Hidaka, Saitama, Japan Correspondence to: Satoshi Inoue, email: [email protected] Keywords: RUNX1, androgen receptor, EZH2, prostate cancer Received: October 02, 2014 Accepted: December 09, 2014 Published: December 10, 2014 This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Androgen receptor (AR) signaling is essential for the development of prostate cancer. Here, we report that runt-related transcription factor (RUNX1) could be a key molecule for the androgen-dependence of prostate cancer. We found RUNX1 is a target of AR and regulated positively by androgen. -
Expression of the Apoptosis-Related Genes Bcl-2 and P53 in Clinical Samples from Endometrial Carcinoma Patients
ANTICANCER RESEARCH 31: 4191-4194 (2011) Expression of the Apoptosis-related Genes Bcl-2 and p53 in Clinical Samples from Endometrial Carcinoma Patients IRENE GONZÁLEZ-RODILLA1, VIRGINIA VERNA2, ANA-BELÉN MUÑOZ2, JOSÉ ESTÉVEZ2, MERCEDES BOIX2 and JOSÉ SCHNEIDER2 Departments of 1Pathology and 2Obstetrics and Gynecology, Marqués de Valdecilla University Hospital, Cantabria University, Santander, Spain Abstract. Background: Although alterations in the mechanisms biological features indicative of a less aggressive tumor of apoptosis are an integral part of the tumor phenotype, their phenotype (1). Furthermore, in that same paper, any level of precise role in endometrial carcinoma is still obscure. The aim expression of Bcl-2, from the lowest upwards, was found to was to determine whether Bcl-2 plays a similar biological role be biologically significant. Finally, an explanation for the so- in endometrial cancer as in breast cancer, endometrial cancer called ‘Bcl-2 paradox in breast cancer’, where Bcl-2 being an being also a hormone-dependent tumor. Materials and anti-apoptotic gene, thus promoting the immortalisation of Methods: The expression of the apoptosis-related Bcl-2 and p53 tumor cells, should in principle represent a negative biological genes, together with Ki67, E-cadherin, c-erb-B2 and estrogen feature of tumors expressing it, virtually all published results and progesterone receptors were studied in 136 formalin-fixed, point to the opposite, i.e. that Bcl-2 expression is associated paraffin-embedded endometrial carcinoma samples by means with a better outcome in breast cancer, was put forward. Bcl- of immunohistochemistry. Results: Bcl-2 expression correlated 2 was found to be predominantly expressed in well- directly and significantly with E-cadherin (r=0.22, p=0.011) differentiated, low-proliferating breast carcinomas expressing estrogen receptor (r=0.18, p=0.04) and progesterone receptor hormone receptors, all of them highly favorable prognostic expression (r=0.30, p=0.0006), and inversely with surgical factors. -
Mutational Landscape and Clinical Outcome of Patients with De Novo Acute Myeloid Leukemia and Rearrangements Involving 11Q23/KMT2A
Mutational landscape and clinical outcome of patients with de novo acute myeloid leukemia and rearrangements involving 11q23/KMT2A Marius Billa,1,2, Krzysztof Mrózeka,1,2, Jessica Kohlschmidta,b, Ann-Kathrin Eisfelda,c, Christopher J. Walkera, Deedra Nicoleta,b, Dimitrios Papaioannoua, James S. Blachlya,c, Shelley Orwicka,c, Andrew J. Carrolld, Jonathan E. Kolitze, Bayard L. Powellf, Richard M. Stoneg, Albert de la Chapelleh,i,2, John C. Byrda,c, and Clara D. Bloomfielda,c aThe Ohio State University Comprehensive Cancer Center, Columbus, OH 43210; bAlliance for Clinical Trials in Oncology Statistics and Data Center, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210; cDivision of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210; dDepartment of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294; eNorthwell Health Cancer Institute, Zucker School of Medicine at Hofstra/Northwell, Lake Success, NY 11042; fDepartment of Internal Medicine, Section on Hematology & Oncology, Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, NC 27157; gDepartment of Medical Oncology, Dana-Farber/Partners Cancer Care, Boston, MA 02215; hHuman Cancer Genetics Program, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210; and iDepartment of Cancer Biology and Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210 Contributed by Albert de la Chapelle, August 28, 2020 (sent for review July 17, 2020; reviewed by Anne Hagemeijer and Stefan Klaus Bohlander) Balanced rearrangements involving the KMT2A gene, located at patterns that include high expression of HOXA genes and thereby 11q23, are among the most frequent chromosome aberrations in contribute to leukemogenesis (14–16). -
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Characterization and Assay of Progesterone Receptor in Human Mammary Carcinoma1
[CANCER RESEARCH 37, 464-471 , February 1977] Characterization and Assay of Progesterone Receptor in Human Mammary Carcinoma1 M. F. Pichon and E. Milgrom Groupe de Recherches sur Ia Biochimie Endocrinienne et Ia Reproduction (INSERM U.135), FacultédeMédecine,Paris-Sud, 94270 Bicétre,France ever, only some patients are improved by such treatments. It SUMMARY would thus be of great practical importance to predict in advance which patient will respond and to nationalize the [3H]Pregn-4-ene-3,20-dione ([3Hjpmogestenane)-recepton choice of the surgical or pharmacological technique to be complexes from human mammary carcinoma were found to used. During the last 15 years, the detection and quantifica be stabilized in the presence of glycerol. The dissociation tion of estrogen receptors in mammary tumors have allowed rate constant was lowered and the equilibrium dissociation marked progress in this direction (11, 12, 16, 18, 21, 22, 34). constant was decreased (KD = 3 nM in the absence of However, the growth of mammary carcinoma may be can glycerol and 1.1 nM in the presence of 30% glycerol), traIled not only by estrogens but also by other hormones whereas no clean-cut effect on the association rate was including observed and no change occurred in the concentration andragens, glucacorticaids, pragestagens , and of binding sites. Gortisol was found to compete with prolactin (13). The study of specific receptors for these [3Hjpmagesterone only at concentrations higher than 1 @M. hormones should shed some bight on the problem of tumor This made it possible to distinguish [3H]pmogestemanebind hormonal dependence . The characterization and measu me ing to the receptor from binding to carticosteroid-binding ment of progesterone receptors have been hampered by the globulin. -
Inhibition of HIF1` Signaling: a Grand Slam for MDS Therapy?
VIEWS IN THE SPOTLIGHT Inhibition of HIF1` Signaling: A Grand Slam for MDS Therapy? Jiahao Chen and Ulrich Steidl Summary: The recent focus on genomics in myelodysplastic syndromes (MDS) has led to important insights and revealed a daunting genetic heterogeneity, which is presenting great challenges for clinical treatment and preci- sion oncology approaches in MDS. Hayashi and colleagues show that multiple mutations frequently found in MDS activate HIF1α signaling, which they also found to be suffi cient to induce overt MDS in mice. Furthermore, both genetic and pharmacologic inhibition of HIF1α suppressed MDS development with only mild effects on normal hematopoiesis, implicating HIF1α signaling as a promising therapeutic target to tackle the heterogeneity of MDS. Cancer Discov; 8(11); 1355–7. ©2018 AACR . See related article by Hayashi et al., p. 1438 (5). Myelodysplastic syndromes (MDS) are a heterogeneous In this issue, Hayashi and colleagues found that target group of hematologic disorders characterized by ineffi cient genes activated by HIF1α signaling were highly expressed in hematopoiesis that manifests as bone marrow (BM) dysplasia a published cohort of 183 patients with MDS compared with and peripheral blood cytopenias, and increased risk of leuke- healthy controls ( 5 ). IHC confi rmed an increased frequency mic transformation ( 1 ). The median survival of patients with of HIF1α-expressing cells in MDS samples at different stages MDS is 4.5 years, with a signifi cantly worse survival of< 1 year (low-, intermediate-, and high-risk) -
Genetic Alterations of Histone Lysine Methyltransferases and Their Significance in Breast Cancer
www.impactjournals.com/oncotarget/ Oncotarget, Vol. 6, No.4 Genetic alterations of histone lysine methyltransferases and their significance in breast cancer Lanxin Liu1,*, Sarah Kimball1,*, Hui Liu1, Andreana Holowatyj1 and Zeng-Quan Yang1 1 Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA * These authors contributed equally to this work Correspondence to: Zeng-Quan Yang, email: [email protected] Keywords: breast cancer, histone lysine methyltransferase, gene amplification, deletion, mutation Received: August 27, 2014 Accepted: December 10, 2014 Published: December 11, 2014 This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Histone lysine methyltransferases (HMTs), a large class of enzymes that catalyze site-specific methylation of lysine residues on histones and other proteins, play critical roles in controlling transcription, chromatin architecture, and cellular differentiation. However, the genomic landscape and clinical significance of HMTs in breast cancer remain poorly characterized. Here, we conducted a meta-analysis of approximately 50 HMTs in breast cancer and identified associations among recurrent copy number alterations, mutations, gene expression, and clinical outcome. We identified 12 HMTs with the highest frequency of genetic alterations, including 8 with high-level amplification, 2 with putative homozygous deletion, and 2 with somatic mutation. Different subtypes of breast cancer have different patterns of copy number and expression for each HMT gene. In addition, chromosome 1q contains four HMTs that are concurrently or independently amplified or overexpressed in breast cancer. Copy number or mRNA expression of several HMTs was significantly associated with basal- like breast cancer and shorter patient survival.