DOCSLIB.ORG

Expression of Estrogen Receptor-Beta Isoforms in Barrett's

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Expression of Estrogen Receptor-Beta Isoforms in Barrett's ANTICANCER RESEARCH 24: 2919-2924 (2004) Expression of Estrogen Receptor-Beta Isoforms in Barrett’s Metaplasia, Dysplasia and Esophageal Adenocarcinoma LIANG LIU, MINNI CHIRALA and MAMOUN YOUNES Departments of Pathology, Baylor College of Medicine and The Methodist Hospital, Houston, TX 77030, U.S.A. Abstract. We have previously shown that the majority of and beta (ER-B). ER-A is mainly expressed in female sex esophageal adenocarcinomas (EA), and its precursor Barrett’s organs, such as breast and uterus (2), whereas ER-B is metaplasia (BM), express estrogen receptor beta (ER-B). Several expressed in both sex organs and other tissues, such as isoforms of ER-B have been described and are presumed to have prostate, lung, thyroid, adrenal cortex and testis (3). Several different functions, but their distribution in BM and EA is not ER-B isoforms have been identified and characterized in known. The aim of this work was to determine which ER-B many non-gynecologic tumors including carcinomas of the isoforms are expressed in EA and BM. Sections of formalin-fixed lung (4), prostate (5), colon (6, 7) and stomach (8). and paraffin-embedded esophageal tissue from 33 esophageactomy Tamoxifen, a specific ER-B antagonist, has been successfully specimens, of which 27 had invasive EA, were stained for the ER- used in the treatment of patients with breast carcinoma B isoforms ER-B1, ER-B2, ER-B3 and ER-B5 utilizing the (9,10) and it has been shown that ER-B status is a significant immunoperoxidase method. ER-B1 was detected in 23 out of 27 predictor of survival in women with breast carcinoma treated (85%) EA compared to 3 out of 14 (21%) Barrett’s metaplasia with mastectomy and adjuvant tamoxifen (11). negative for dysplasia (BMND) (p=0.0001); ER-B2 was expressed The incidence of esophageal adenocarcinoma has been rising in 22 out of 27 (81%) EA in contrast to 3 out of 14 (21%) BMND in the United States and Western Europe since the 1970s (12). (p=0.0004); ER-B3 was positive in 27 out of 27 (100%) EA in Despite advances in cancer therapy, mortality of this cancer contrast to only 1 out of 14 (7%) BMND (p<0001); ER-B5 was remains high with an overall 2-year survival of only 20% detected in 27 out of 27 (100%) EA compared to 9 out of 14 (12,13). We recently showed that ER-B is expressed in Barrett’s (62%) of BMND (p=0.0027). High- and low-grade dysplasia metaplasia and associated esophageal adenocarcinoma (14), showed a similar ER-beta isoform expression profile to that of EA. raising the possibility that EA may respond to treatment with Cancers invasive through the esophageal wall had a higher percent antiestrogens. The purpose of this study was to determine which of cells with cytoplasmic expression of ER-B1 than tumors limited ER-B isoforms are expressed in esophageal adenocarcinomas. to the wall (T3 vs. T1 and T2, p=0.051). We conclude that ER- B1, ER-B2, ER-B3 and ER-B5 are overexpressed in EA compared Materials and Methods to its precursor lesion BMND, suggesting a significant biological role for steroid hormones in EA. This study was approved by the Institutional Review Board for Baylor College of Medicine and Affiliated Hospitals. Estrogen receptors (ER) are intracellular protein receptors Sections of formalin-fixed and paraffin-embedded tissue from activated by estradiol to initiate serial reactions associated 32 randomly selected esophagectomy cases were used in this study. Of these cases, 27 had esophageal adenocarcinoma (EA), 11 high- with cell differentiation and proliferation (1). ERs are grade dysplasia (HGD), 14 low-grade dysplasia (LGD) and 14 of classified into two subtypes, estrogen receptor alpha (ER-A) Barrett’s metaplasia negative for dysplasia (BMND). The expression of ER-B isoforms was determined by immunoperoxidase staining as we have recently described (15), utilizing a DAKO automated immunostainer (DAKO Corporation, Correspondence to: Mamoun Younes, M.D., Department of Carpinteria, CA, USA). The tissue sections were evaluated for ER- Pathology, Baylor College of Medicine, One Baylor Plaza, B isoform immunoreactivity, which was scored as follows: 0 (0%), Houston, TX 77030, U.S.A. Tel: (713) 394-6485, Fax: (713) 793- 1(1% to 10%), 2 (11% to 25%), 3 (26% to 50%), 4 (51% to 75%) 1603, e-mail: [email protected] and 5 (>75%). Nuclear and cytoplasmic immunoreactivity were determined separately. Statistical analysis (Fisher’s exact test and Key Words: Estrogen receptor beta, esophagus cancer, Barrett’s unpaired t-test) was performed utilizing InStat version 3.0a metaplasia. software (GraphPad Software, San Diego, CA, USA). 0250-7005/2004 $2.00+.40 2919 ANTICANCER RESEARCH 24: 2919-2924 (2004) Table I. Expression of estrogen receptor beta isoforms 1, 2, 3 and 5 in Endothelial cells and nerves were always positive for ER- esophageal adenoarcinoma (EA), high-grade dysplasia (HGD), low-grade B2, as reported previously in breast tissues (15). dysplasia (LGD) and Barrett’s metaplasia negative for dysplasia (BMND). ER-B3 was detected in 100% of EA (27/27), 91% of HGD EA HGD LGD BMND p (EA vs. (10/11), 93% of LGD (13/14) but only 7% (1/14) in BMND, BMND) and it showed more nuclear (52%) than cytoplasmic (22%) distribution in cases of EA. Although many mitotic figures ER-B1 85% 73% 57% 21% 0.0001 were positive for ER-B3, not all mitoses were positive, and (23/27) (8/11) (8/14) (3/14) some nuclei that were not in mitosis were also positive. There ER-B2 81% 73% 50% 21% 0.0004 was no significant correlation between the percent of ER-B3- (22/27) (8/11) (7/14) (3/14) positive cancer cells and the number of mitotic figures per 10 high power microscopic fields (proliferative activity). ER-B3 100% 91% 93% 7% <0.0001 ER-B5 was expressed in 100% of EA (27/27), 100% of (27/27) (10/11) (13/14) (1/14) HGD (11/11), 93% of LGD (13/14) and in 64% of BMND ER-B5 100% 100% 93% 62% 0.0027 (9/14). Unlike the other isoforms, ER-B5 showed more (27/27) (11/11) (13/14) (9/14) nuclear pattern of expression (52%) and less cytoplasmic pattern (4%) in cases of EA, and was negative in mitosis. ER-B1, ER-B2, ER-B3 and ER-B5 were expressed in significantly more cases of EA than in its precursor lesion Results BMND (p=0.0001, p=0.0004, p<0001and p=0.0027, respectively), suggesting a significant role for steroid ER-B isoforms immunoreactivity in esophageal hormones in the development and maintenance of EA. adenocarcinoma (EA), high-grade dysplasia (HGD), low- In all cases of BMND, all isoforms showed only nuclear grade dysplasia (LGD) and BMND is detailed in Table I and expression, whereas cytoplasmic expression was seen in the intracellulr distribution of these isoforms in the positive dysplasia and adenocarcinoma (Table II). cases is shown in Table II and Figure 1. The percentage of There was no correlation between the expression of any of ER-B-positive cells in EA is detailed in Figure 2. the ER-B isoforms and tumor proliferative activity, ER-B1 is expressed in 23 out of 27 (85%) EA, 8 out of 11 determined as the number of mitotic figures in 10 consecutive (73%) HGD, 8 out of 14 (57%) LGD and 3 out of 14 (21%) high-power microscopic fields, or with lymph node metastasis. BMND. Slightly more cancers showed cytoplasmic ER-B1 Tumors invasive through the wall of the esophagus (pT3) had immunoreactivity (44%) than nuclear immunoreactivity a higher cytoplasmic ER-B1 score (mean 3.4, median score (30%). ER-B1 was not expressed in any mitotic figures. 4) than tumors limited to the wall (pT1 and pT2, mean 1.7, Occasional stromal cells and rare blood vessels (endothelium) median 0) and the difference almost reached statistical were positive for ER-B1, but nerves were always negative. significance (p=0.051, unpaired t-test, two-tailed). ER-B2 was positive in 22 out of 27 (81%) EA, 8 out of 11 (73%) HGD, 7 out of 14 (50%) LGD and 3 out of 14 Discussion (21%) BMND. In EA, ER-B2 immunoreactivity was cytoplasmic in most cases (73%) and nuclear in only a few The incidence of esophageal adenocarcinoma (EA) in the (9%). ER-B2 was not detected in any mitotic figures. United States has been steadily increasing since the mid Table II. Differential expression of estrogen receptor beta isoforms 1, 2, 3 and 5 in positive cases of adenoarcinoma (EA), high-grade dysplasia (HGD), low-grade dysplasia (LGD) and Barrett’s esophagus negative for dysplasia (BMND). EA HGD LGD BMND N1 C2 N&C3 N C N&C N C N&C N C N&C ER-B1 30% 44% 26% 75% 12.5% 12.5% 75% 0 25% 100% 0 0 ER-B2 9% 73% 18% 62.5% 25% 12.5% 71% 29% 0 100% 0 0 ER-B3 52% 22% 26% 80% 10% 10% 77% 15% 8% 100% 0 0 ER-B5 52% 4% 44% 100% 0 0 100% 0 0 100% 0 0 1. N: nuclear only 2. C: cytoplasmic only 3. N&C: both nuclear and cytoplasmic 2920 Liu et al: Estrogen Receptor Beta Isoforms in Barrett’s and Esophageal Adenocarcinoma Figure 1. Examples of immunohistochemical staining for ER-B isoforms in esophageal adenocarcinoma: (A) nuclear staining, (B) cytoplasmic staining, (C) nuclear and cytoplasmic staining and (D) staining in mitosis, seen only in some cases with ER-B3. only 25% of patients surviving 3 years after surgical resection (12).
Load more

Recommended publications
  • Analysis of Estrogen Receptor Isoforms and Variants in Breast Cancer Cell Lines
    EXPERIMENTAL AND THERAPEUTIC MeDICINE 2: 537-544, 2011 Analysis of estrogen receptor isoforms and variants in breast cancer cell lines MAIE AL-BADER1, CHRISTOPHER FORD2, BUSHRA AL-AYADHY3 and ISSAM FRANCIS3 Departments of 1Physiology, 2Surgery, and 3Pathology, Faculty of Medicine, Kuwait University, Safat 13110, Kuwait Received November 22, 2010; Accepted February 14, 2011 DOI: 10.3892/etm.2011.226 Abstract. In the present study, the expression of estrogen domain C, the DNA binding domain; domains D/E, bearing receptor (ER)α and ERβ isoforms in ER-positive (MCF7, both the activation function-2 (AF-2) and the ligand binding T-47D and ZR-75-1) and ER-negative (MDA-MB-231, SK-BR-3, domains; and finally, domain F, the C-terminal domain (6,7). MDA-MB-453 and HCC1954) breast cancer cell lines was The actions of estrogens are mediated by binding to ERs investigated. ERα mRNA was expressed in ER-positive and (ERα and/or ERβ). These receptors, which are co-expressed some ER-negative cell lines. ERα ∆3, ∆5 and ∆7 spliced in a number of tissues, form functional homodimers or variants were present in MCF7 and T-47D cells; ERα ∆5 heterodimers. When bound to estrogens as homodimers, the and ∆7 spliced variants were detected in ZR-75-1 cells. transcription of target genes is activated (8,9), while as heterodi- MDA-MB-231 and HCC1954 cells expressed ERα ∆5 and ∆7 mers, ERβ exhibits an inhibitory action on ERα-mediated gene spliced variants. The ERβ1 variant was expressed in all of the expression and, in many instances, opposes the actions of ERα cell lines and the ERβ2 variant in all of the ER-positive and (7,9).
    [Show full text]
  • Common Single-Nucleotide Polymorphisms in the Estrogen Receptor B Promoter Are Associated with Colorectal Cancer Survival in Postmenopausal Women
    Published OnlineFirst November 13, 2012; DOI: 10.1158/0008-5472.CAN-12-2484 Cancer Prevention and Epidemiology Research Common Single-Nucleotide Polymorphisms in the Estrogen Receptor b Promoter Are Associated with Colorectal Cancer Survival in Postmenopausal Women Michael N. Passarelli1,2, Amanda I. Phipps1, John D. Potter1,2,3, Karen W. Makar1, Anna E. Coghill1,2, Karen J. Wernli3,4, Emily White1,2, Andrew T. Chan5,6, Carolyn M. Hutter1,2, Ulrike Peters1,2, and Polly A. Newcomb1,2 Abstract Loss of estrogen receptor b (ERb) expression in the gut is associated with colorectal cancer (CRC) initiation and progression. Germline single-nucleotide polymorphisms (SNP) in genes for the sex-steroid hormone receptors are not strongly associated with CRC risk; however, these SNPs have not previously been evaluated in relation to survival after diagnosis. We enrolled 729 women, ages 50 to 74, diagnosed with invasive CRC between 1997 and 2002 in 13 counties covered by the Seattle-Puget Sound Surveillance Epidemiology and End Results cancer registry. Participants provided germline DNA. We selected 99 tag-SNPs for the androgen receptor (AR), ERa (ESR1), ERb (ESR2), and progesterone receptor (PGR) genes. Mortality outcomes were ascertained from the National Death Index. During a median of 6.6 years of follow-up, 244 deaths occurred (161 from CRC). We identified 20 SNPs (12 of ESR2 and 8 of PGR) for replication in 1,729 women diagnosed with incident invasive CRC (555 deaths; 405 from CRC) from three prospective cohort studies that participate in the Genetics and Epidemiology of Colorectal Cancer Consortium. Three correlated SNPs in the promoter of ESR2 (rs2987983, rs3020443, and rs2978381) were statistically significant predictors of CRC-specific and overall survival.
    [Show full text]
  • Irf1) Signaling Regulates Apoptosis and Autophagy to Determine Endocrine Responsiveness and Cell Fate in Human Breast Cancer
    INTERFERON REGULATORY FACTOR-1 (IRF1) SIGNALING REGULATES APOPTOSIS AND AUTOPHAGY TO DETERMINE ENDOCRINE RESPONSIVENESS AND CELL FATE IN HUMAN BREAST CANCER A Dissertation Submitted to the Faculty of the Graduate School of Arts and Sciences of Georgetown University in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Physiology & Biophysics By Jessica L. Roberts, B.S. Washington, DC September 27, 2013 Copyright 2013 by Jessica L. Roberts All Rights Reserved ii INTERFERON REGULATORY FACTOR-1 (IRF1) SIGNALING REGULATES APOPTOSIS AND AUTOPHAGY TO DETERMINE ENDOCRINE RESPONSIVENESS AND CELL FATE IN HUMAN BREAST CANCER Jessica L. Roberts, B.S. Thesis Advisor: Robert Clarke, Ph.D. ABSTRACT Interferon regulatory factor-1 (IRF1) is a nuclear transcription factor and pivotal regulator of cell fate in cancer cells. While IRF1 is known to possess tumor suppressive activities, the role of IRF1 in mediating apoptosis and autophagy in breast cancer is largely unknown. Here, we show that IRF1 inhibits antiapoptotic B-cell lymphoma 2 (BCL2) protein expression, whose overexpression often contributes to antiestrogen resistance. We proposed that directly targeting the antiapoptotic BCL2 members with GX15-070 (GX; obatoclax), a BH3-mimetic currently in clinical development, would be an attractive strategy to overcome antiestrogen resistance in some breast cancers. Inhibition of BCL2 activity, through treatment with GX, was more effective in reducing the cell density of antiestrogen resistant breast cancer cells versus sensitive cells, and this increased sensitivity correlated with an accumulation of autophagic vacuoles. While GX treatment promoted autophagic vacuole and autolysosome formation, p62/SQSTM1, a marker for autophagic degradation, levels accumulated.
    [Show full text]
  • Estrogen Receptor-Dependent Regulation of Dendritic Cell Development and Function
    REVIEW published: 10 February 2017 doi: 10.3389/fimmu.2017.00108 Estrogen Receptor-Dependent Regulation of Dendritic Cell Development and Function Sophie Laffont1*, Cyril Seillet2,3 and Jean-Charles Guéry1* 1 Centre de Physiopathologie de Toulouse Purpan (CPTP), Université de Toulouse, INSERM, CNRS, UPS, Toulouse, France, 2 Division of Molecular Immunology, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia, 3 Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia Autoimmunity, infectious diseases and cancer affect women and men differently. Because they tend to develop more vigorous adaptive immune responses than men, women are less susceptible to some infectious diseases but also at higher risk of autoimmunity. The regulation of immune responses by sex-dependent factors probably involves several non-redundant mechanisms. A privileged area of study, however, concerns the role of sex steroid hormones in the biology of innate immune cells, especially dendritic cells (DCs). In recent years, our understanding of the lineage origin of DC populations has expanded, Edited by: and the lineage-committing transcription factors shaping peripheral DC subsets have Manfred B. Lutz, been identified. Both progenitor cells and mature DC subsets express estrogen receptors University of Würzburg, Germany (ERs), which are ligand-dependent transcription factors. This suggests that estrogens Reviewed by: may contribute to the reported sex differences in immunity by regulating DC biology. Meredith O’Keeffe, Monash University, Australia Here, we review the recent literature and highlight evidence that estrogen-dependent Pieter J. M. Leenen, activation of ERα regulates the development or the functional responses of particular DC Erasmus University Rotterdam, + Netherlands subsets.
    [Show full text]
  • Estrogen Modulates Transactivations of SXR-Mediated Liver X Receptor Response Element and CAR-Mediated Phenobarbital Response Element in Hepg2 Cells
    EXPERIMENTAL and MOLECULAR MEDICINE, Vol. 42, No. 11, 731-738, November 2010 Estrogen modulates transactivations of SXR-mediated liver X receptor response element and CAR-mediated phenobarbital response element in HepG2 cells Gyesik Min1 by moxestrol in the presence of ER. Thus, ER may play both stimulatory and inhibitory roles in modulating Department of Pharmaceutical Engineering CAR-mediated transactivation of PBRU depending on Jinju National University the presence of their ligands. In summary, this study Jinju 660-758, Korea demonstrates that estrogen modulates transcriptional 1Correspondence: Tel, 82-55-751-3396; activity of SXR and CAR in mediating transactivation Fax, 82-55-751-3399; E-mail, [email protected] of LXRE and PBRU, respectively, of the nuclear re- DOI 10.3858/emm.2010.42.11.074 ceptor target genes through functional cross-talk be- tween ER and the corresponding nuclear receptors. Accepted 14 September 2010 Available Online 27 September 2010 Keywords: constitutive androstane receptor; estro- gen; liver X receptor; phenobarbital; pregnane X re- Abbreviations: CAR, constitutive androstane receptor; CYP, cyto- ceptor; transcriptional activation chrome P450 gene; E2, 17-β estradiol; ER, estrogen receptor; ERE, estrogen response element; GRIP, glucocorticoid receptor interacting protein; LRH, liver receptor homolog; LXR, liver X receptor; LXREs, LXR response elements; MoxE2, moxestrol; PB, Introduction phenobarbital; PBRU, phenobarbital-responsive enhancer; PPAR, Estrogen plays important biological functions not peroxisome proliferator activated receptor; RXR, retinoid X receptor; only in the development of female reproduction SRC, steroid hormone receptor coactivator; SXR, steroid and and cellular proliferation but also in lipid meta- xenobiotic receptor; TCPOBOP, 1,4-bis-(2-(3,5-dichloropyridoxyl)) bolism and biological homeostasis in different tis- benzene sues of body (Archer et al., 1986; Croston et al., 1997; Blum and Cannon, 2001; Deroo and Korach, 2006; Glass, 2006).
    [Show full text]
  • Stromal Cell Signature Associated with Response to Neoadjuvant Chemotherapy in Locally Advanced Breast Cancer
    cells Article Stromal Cell Signature Associated with Response to Neoadjuvant Chemotherapy in Locally Advanced Breast Cancer 1, 2, 3 Maria Lucia Hirata Katayama y, René Aloísio da Costa Vieira y, Victor Piana Andrade , Rosimeire Aparecida Roela 1, Luiz Guilherme Cernaglia Aureliano Lima 3, Ligia Maria Kerr 4, Adriano Polpo de Campos 5,6, Carlos Alberto de Bragança Pereira 7, Pedro Adolpho de Menezes Pacheco Serio 1, Giselly Encinas 1, Simone Maistro 1, Matheus de Almeida Leite Petroni 1, Maria Mitzi Brentani 1 and Maria Aparecida Azevedo Koike Folgueira 1,* 1 Departamento de Radiologia e Oncologia, Centro de Investigação Translacional em Oncologia, Instituto do Cancer do Estado de Sao Paulo, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 01246-000, SP, Brazil; [email protected] (M.L.H.K.); [email protected] (R.A.R.); [email protected] (P.A.d.M.P.S.); [email protected] (G.E.); [email protected] (S.M.); [email protected] (M.d.A.L.P.); [email protected] (M.M.B.) 2 Departamento de Mastologia, Hospital de Câncer de Barretos, Barretos 14.784-400, SP, Brazil; [email protected] 3 A.C. Camargo Cancer Center, Sao Paulo 01525-001, SP, Brazil; [email protected] (V.P.A.); [email protected] (L.G.C.A.L.) 4 Departamento de Patologia, Hospital de Câncer de Barretos, Barretos 14.784-400, SP, Brazil; [email protected] 5 Departamento de Estatística, Centro de Ciências Exatas e de Tecnologia, Universidade Federal de São Carlos, Sao Carlos 13565-905, SP, Brazil; [email protected] 6 Department of Mathematics and Statistics, The University of Western Australia, M019, 35 Stirling Highway, 6009 Crawley, WA, Australia 7 Departamento de Estatística, Instituto de Matemática e Estatística, Universidade de São Paulo, São Paulo 05508-090, SP, Brazil; [email protected] * Correspondence: [email protected] These authors participated equally in this work.
    [Show full text]
  • Role of Estrogen Receptor-Β in Endometriosis
    39 Role of Estrogen Receptor-β in Endometriosis Serdar E. Bulun, M.D. 1 Diana Monsavais, B.S. 1 Mary Ellen Pavone, M.D. 1 Matthew Dyson, Ph.D. 1 Qing Xue, M.D., Ph.D. 2 Erkut Attar, M.D. 3 Hideki Tokunaga, M.D., Ph.D. 4 Emily J. Su, M.D., M.S. 1 1 Division of Reproductive Biology Research, Department Obstetrics Address for correspondence and reprint requests Serdar E. Bulun, and Gynecology, Northwestern University Feinberg School of M.D., Division of Reproductive Biology Research, Department Medicine, Chicago, Illinois Obstetrics and Gynecology, Northwestern University Feinberg School 2 Department of Obstetrics and Gynecology, First Hospital of Peking of Medicine, 303 E. Superior Street, 4-123, Chicago, IL 60611 University, Beijing, P.R. China (e-mail: [email protected]). 3 Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Istanbul University Capa School of Medicine, Istanbul, Turkiye 4 Department of Obstetrics and Gynecology, Tohoku University School of Medicine, Sendai, Japan Semin Reprod Med 2012; 30:39–45 Abstract Endometriosis is an estrogen-dependent disease. The biologically active estrogen, estradiol, aggravates the pathological processes (e.g., inflammation and growth) and the symptoms (e.g., pain) associated with endometriosis. Abundant quantities of estradiol are available for endometriotic tissue via several mechanisms including local Keywords aromatase expression. The question remains, then, what mediates estradiol action. ► ER-β Because estrogen receptor (ER)β levels in endometriosis are >100 times higher than ► nuclear receptor those in endometrial tissue, this review focuses on this nuclear receptor. Deficient ► estrogen methylation of the ERβ promoter results in pathological overexpression of ERβ in ► DNA methylation endometriotic stromal cells.
    [Show full text]
  • Artin TARGETING ESTROGEN RECEPTOR AS a STRATEGY for PERSONALIZED MEDICINE in OVARIAN CANCER by Courtney Lynn Andersen A.A., Libe
    TARGETING ESTROGEN RECEPTOR AS A STRATEGY FOR PERSONALIZED MEDICINE IN OVARIAN CANCER by Courtney Lynn Andersen A.A., Liberal Arts & Sciences, Middlesex Community College, 2008 B.S., Biological Sciences, University of Massachusetts Lowell, 2011 Submitted to the Graduate Faculty of the School of Medicine in partial fulfillment of the requirements for the degree of PhD in Molecular Pharmacology University of Pittsburgh artin 2016 UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE This dissertation was presented by Courtney L. Andersen It was defended on February 16, 2016 and approved by Don DeFranco, PhD, Professor, Pharmacology & Chemical Biology Adrian Lee, PhD, Professor, Pharmacology & Chemical Biology, Anda Vlad, MD, PhD, Professor, Obstetrics, Gynecology, & Reproductive Sciences Robert Edwards, MD, Chair, Obstetrics and Gynecology, Magee-Womens Hospital of UPMC Dissertation Advisor: Steffi Oesterreich, PhD, Professor, Pharmacology & Chemical Biology ii Copyright © by Courtney L. Andersen 2016 iii TARGETING ESTROGEN RECEPTOR AS A STRATEGY FOR PERSONALIZED MEDICINE IN OVARIAN CANCER Courtney L. Andersen, PhD University of Pittsburgh, 2016 Ovarian cancer comprises a diverse set of diseases that are difficult to detect and treat successfully. Improving outcomes for ovarian cancer patients is contingent upon identifying targeted, individualized therapeutic strategies. One promising but under-utilized target is estrogen receptor-alpha (ER). ER is expressed in ~70% of epithelial ovarian cancers and epidemiologic studies implicate a role for estrogen in ovarian tumorigenesis. Further, clinical data suggest that a subset of ovarian cancer patients benefit from endocrine therapy. We hypothesized that ER drives development and progression of a subset of ovarian tumors and that outputs of ER function would identify patients who respond to endocrine therapy.
    [Show full text]
  • Epigenetic Alterations in Triple-Negative Breast Cancer—The Critical Role of Extracellular Matrix
    cancers Review Epigenetic Alterations in Triple-Negative Breast Cancer—The Critical Role of Extracellular Matrix Vasiliki Zolota 1,*, Vasiliki Tzelepi 1 , Zoi Piperigkou 2,3 , Helen Kourea 1, Efthymia Papakonstantinou 4, Maria-Ioanna Argentou 5 and Nikos K. Karamanos 2,3 1 Department of Pathology, School of Medicine, University of Patras, 26504 Rion, Greece; [email protected] (V.T.); [email protected] (H.K.) 2 Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, 26110 Patras, Greece; [email protected] (Z.P.); [email protected] (N.K.K.) 3 Foundation for Research and Technology-Hellas (FORTH)/Institute of Chemical Engineering Sciences (ICE-HT), 26110 Patras, Greece 4 Department of Gynecology and Obstetrics School of Medicine, University of Patras, 26504 Rion, Greece; [email protected] 5 Department of Surgery, School of Medicine, University of Patras, 26504 Rion, Greece; [email protected] * Correspondence: [email protected]; Tel.: +30-0693613366 Simple Summary: Current data suggest that epigenetic alterations are involved in the initiation and subclonal evolution of breast cancer. During cancer progression, the extracellular matrix undergoes significant structural alterations and the epithelial–mesenchymal transition is induced. These events among other processes are closely related with the epigenetic modifiers. Triple-negative breast cancer is an aggressive molecular subgroup characterized by genomic complexity and limited Citation: Zolota, V.; Tzelepi, V.; therapeutic options. Recent knowledge indicates that matrix alterations in triple-negative cancer Piperigkou, Z.; Kourea, H.; cells are epigenetically regulated and that matrix-associated events collectively increase tumor cell Papakonstantinou, E.; Argentou, M.-I.; Karamanos, N.K.
    [Show full text]
  • The Genetic Background of Endometriosis: Can ESR2 and CYP19A1 Genes Be a Potential Risk Factor for Its Development?
    International Journal of Molecular Sciences Review The Genetic Background of Endometriosis: Can ESR2 and CYP19A1 Genes Be a Potential Risk Factor for Its Development? Beata Smolarz 1,* , Krzysztof Szyłło 2 and Hanna Romanowicz 1 1 Laboratory of Cancer Genetics, Department of Pathology, Polish Mother’s Memorial Hospital Research Institute, Rzgowska 281/289, 93-338 Lodz, Poland; [email protected] 2 Department of Operative Gynaecology and Oncological Gynaecology, Polish Mother’s Memorial Hospital Research Institute, Rzgowska 281/289, 93-338 Lodz, Poland; [email protected] * Correspondence: [email protected]; Tel.: +48-42-271-12-90 Received: 21 September 2020; Accepted: 2 November 2020; Published: 3 November 2020 Abstract: Endometriosis is defined as the presence of endometrial foci, localized beyond their primary site, i.e., the uterine cavity. The etiology of this disease is rather complex. Its development is supported by hormonal, immunological, and environmental factors. During recent years, particular attention has been focused on the genetic mechanisms that may be of particular significance for the increased incidence rates of endometriosis. According to most recent studies, ESR2 and CYP19A1 genes may account for the potential risk factors of infertility associated with endometriosis. The paper presents a thorough review of the latest reports and data concerning the genetic background of the risk for endometriosis development. Keywords: endometriosis; genes; ESR2; CYP19A1; polymorphism; expression 1. Introduction Endometriosis is a medical condition characterized by the presence of active foci of uterine mucous membrane (glandular and stromal cells) or of endometrial tissue cells (endometrioides, where eides means “similar” in Greek) localized beyond the uterine cavity, i.e., in the muscular layer of the uterus as well as in other genital organs and at their regions, and even at other places of the body, distant from the genital organs [1].
    [Show full text]
  • KLF4 Suppresses Estrogen-Dependent Breast Cancer Growth by Inhibiting the Transcriptional Activity of Era
    Oncogene (2009) 28, 2894–2902 & 2009 Macmillan Publishers Limited All rights reserved 0950-9232/09 $32.00 www.nature.com/onc ORIGINAL ARTICLE KLF4 suppresses estrogen-dependent breast cancer growth by inhibiting the transcriptional activity of ERa K Akaogi1, Y Nakajima1, I Ito1, S Kawasaki1, S-h Oie1, A Murayama1,2,3, K Kimura1 and J Yanagisawa1,2 1Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba Science City, Ibaraki, Japan; 2TARA Center, University of Tsukuba, Tsukuba Science City, Ibaraki, Japan and 3PRESTO, JST, 4-1-8 Honcho Kawaguchi, Saitama, Japan Kruppel-like factor 4 (KLF4) is a transcription factor that et al., 1999, 2000; Nickenig et al., 2002; Chen et al., participates in both tumor suppression and oncogenesis. 2003). This indicates that KLF4 regulates the expression To determine the association of KLF4 with tumorigenesis, of a set of cell-cycle genes to coordinately inhibit cellular we integrated data assembled in the Oncomine database proliferation. in vivo, KLF4 is essential for maintaining and discovered a decrease in KLF4 gene transcripts in terminally differentiated epithelial cells in the lung, skin breast cancers. Further analysis of the database also and gastrointestinal tract (Shields et al., 1996; Segre showed a correlation between KLF4 expression and et al., 1999; Jaubert et al., 2003; Blanchon et al., 2006; estrogen receptor-a (ERa) positivity. Knockdown of Patel et al., 2006). In cultured cells, KLF4 expression is KLF4 in MCF-7 cells elevated the growth rate of these temporally associated with conditions that promote cells in the presence of estrogen. Therefore, we examined growth arrest, such as serum deprivation, contact the interaction between KLF4 and ERa, and found that inhibition and DNA damage, and constitutive KLF4 KLF4 bound to the DNA-binding region of ERa.
    [Show full text]
  • Estrogen Receptor Phosphorylation Deborah A
    Steroids 68 (2003) 1–9 Review Estrogen receptor phosphorylation Deborah A. Lannigan∗ Center for Cell Signaling, Health Sciences Center, University of Virginia, Hospital West, Room 7041, Box 800577, Charlottesville, VA 22908-0577, USA Received 30 April 2002; accepted 13 June 2002 Abstract Estrogen receptor ␣ (ER␣) is phosphorylated on multiple amino acid residues. For example, in response to estradiol binding, human ER␣ is predominately phosphorylated on Ser-118 and to a lesser extent on Ser-104 and Ser-106. In response to activation of the mitogen-activated protein kinase pathway, phosphorylation occurs on Ser-118 and Ser-167. These serine residues are all located within the activation function 1 region of the N-terminal domain of ER␣. In contrast, activation of protein kinase A increases the phosphorylation of Ser-236, which is located in the DNA-binding domain. The in vivo phosphorylation status of Tyr-537, located in the ligand-binding domain, remains controversial. In this review, I present evidence that these phosphorylations occur, and identify the kinases thought to be responsible. Additionally, the functional importance of ER␣ phosphorylation is discussed. © 2002 Elsevier Science Inc. All rights reserved. Keywords: Estrogen receptor; Phosphorylation; Transcription 1. Overview There are two known ER isoforms, ␣ and ␤, which dif- fer in their ligand specificities and physiological functions This review will focus on the major phosphorylation sites [17–19]. There are also a number of splice variants for each in estrogen receptor ␣ (ER␣) that occur in response to ei- of the isoforms, some of which influence the activity of the ther estradiol or through the activation of second messen- wild type receptor [20–23].
    [Show full text]