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Ferro A, Campora M, Caldara A, De Lisi D, Lorenzi M, Monteverdi S, Mihai R, Bisio A, Dipasquale M, Caffo O, Ciribilli Y. Novel Treatment Strategies for Hormone Receptor (HR)-Positive, HER2-Negative Metastatic Breast Cancer. J Clin Med 2024; 13:3611. [PMID: 38930141 PMCID: PMC11204965 DOI: 10.3390/jcm13123611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 06/11/2024] [Accepted: 06/18/2024] [Indexed: 06/28/2024] Open
Abstract
Estrogen receptor (ER)-positive breast cancer (BC) is the most common BC subtype. Endocrine therapy (ET) targeting ER signaling still remains the mainstay treatment option for hormone receptor (HR)-positive BC either in the early or in advanced setting, including different strategies, such as the suppression of estrogen production or directly blocking the ER pathway through SERMs-selective estrogen receptor modulators-or SERDs-selective estrogen receptor degraders. Nevertheless, the development of de novo or acquired endocrine resistance still remains challenging for oncologists. The use of novel ET combined with targeted drugs, such as cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, has significantly improved long-term outcome rates, thus changing the therapeutic algorithm for metastatic BC (MBC) and recently the therapeutic strategy in the adjuvant setting for early high-risk BC. Eluding the resistance to CDK4/6 inhibitors combined with ET is currently an unmet medical need, and there is disagreement concerning the best course of action for patients who continue to progress after this combination approach. Genetic changes in the tumor along its growth uncovered by genomic profiling of recurrent and/or metastatic lesions through tumor and/or liquid biopsies may predict the response or resistance to specific agents, suggesting the best therapeutic strategy for each patient by targeting the altered ER-dependent pathway (novel oral SERDs and a new generation of anti-estrogen agents) or alternative ER-independent signaling pathways such as PI3K/AKT/mTOR or tyrosine kinase receptors (HER2 mutations or HER2 low status) or by inhibiting pathways weakened through germline BRCA1/2 mutations. These agents are being investigated as single molecules and in combination with other target therapies, offering promising weapons to overcome or avoid treatment failure and propose increasingly more personalized treatment approaches. This review presents novel insights into ET and other targeted therapies for managing metastatic HR+/HER2- BC by exploring potential strategies based on clinical evidence and genomic profiling following the failure of the CDK4/6i and ET combination.
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Affiliation(s)
- Antonella Ferro
- Medical Oncology and Breast Unit, Santa Chiara Hospital, APSS Trento, 38122 Trento, Italy; (A.C.); (D.D.L.); (M.L.); (S.M.); (M.D.)
| | - Michela Campora
- Department of Pathology, Santa Chiara Hospital, APSS Trento, 38122 Trento, Italy;
| | - Alessia Caldara
- Medical Oncology and Breast Unit, Santa Chiara Hospital, APSS Trento, 38122 Trento, Italy; (A.C.); (D.D.L.); (M.L.); (S.M.); (M.D.)
| | - Delia De Lisi
- Medical Oncology and Breast Unit, Santa Chiara Hospital, APSS Trento, 38122 Trento, Italy; (A.C.); (D.D.L.); (M.L.); (S.M.); (M.D.)
| | - Martina Lorenzi
- Medical Oncology and Breast Unit, Santa Chiara Hospital, APSS Trento, 38122 Trento, Italy; (A.C.); (D.D.L.); (M.L.); (S.M.); (M.D.)
| | - Sara Monteverdi
- Medical Oncology and Breast Unit, Santa Chiara Hospital, APSS Trento, 38122 Trento, Italy; (A.C.); (D.D.L.); (M.L.); (S.M.); (M.D.)
| | - Raluca Mihai
- Department of Pathology, Queen Elizabeth University Hospital, Glasgow G51 4TF, UK;
| | - Alessandra Bisio
- Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, 38123 Trento, Italy; (A.B.); (Y.C.)
| | - Mariachiara Dipasquale
- Medical Oncology and Breast Unit, Santa Chiara Hospital, APSS Trento, 38122 Trento, Italy; (A.C.); (D.D.L.); (M.L.); (S.M.); (M.D.)
| | - Orazio Caffo
- Medical Oncology, Santa Chiara Hospital, APSS Trento, 38122 Trento, Italy;
| | - Yari Ciribilli
- Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, 38123 Trento, Italy; (A.B.); (Y.C.)
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Ezenwafor TC, Uzonwanne VO, Madukwe JUA, Amin SM, Anye VC, Obayemi JD, Odusanya OS, Soboyejo WO. Adhesion of LHRH/EphA2 to human Triple Negative Breast Cancer tissues. J Mech Behav Biomed Mater 2022; 136:105461. [PMID: 36195050 DOI: 10.1016/j.jmbbm.2022.105461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 08/26/2022] [Accepted: 09/08/2022] [Indexed: 11/19/2022]
Abstract
The adhesive interactions between molecular recognition units (such as specific peptides and antibodies) and antigens or other receptors on the surfaces of tumors are of great value in the design of targeted nanoparticles and drugs for the detection and treatment of specific cancers. In this paper, we present the results of a combined experimental and theoretical study of the adhesion between Luteinizing Hormone Releasing Hormone (LHRH)/Epherin type A2 (EphA2)-AFM coated tips and LHRH/EphA2 receptors that are overexpressed on the surfaces of human Triple Negative Breast Cancer (TNBC) tissues of different histological grades. Following a histochemical and immuno-histological study of human tissue extracts, the receptor overexpression, and their distributions are characterized using Immunohistochemistry (IHC), Immunofluorescence (IF), and a combination of fluorescence microscopy and confocal microscopy. The adhesion forces between LHRH or EphA2 and human TNBC breast tissues are measured using force microscopy techniques that account for the potential effects of capillary forces due to the presence of water vapor. The corresponding adhesion energies are also determined using adhesion theory. The pull off forces and adhesion energies associated with higher grades of TNBC are shown to be greater than those associated with normal/non-tumorigenic human breast tissues, which were studied as controls. The observed increase in adhesion forces and adhesion energies are also correlated with the increasing incidence of LHRH/EphA2 receptors at higher grades of TNBC. The implications of the results are discussed for the development of targeted nanostructures for the detection and treatment of TNBC.
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Affiliation(s)
- Theresa C Ezenwafor
- Department of Materials Science and Engineering, African University of Science and Technology, Km 10 Airport Road, Galadimawa, Abuja, Federal Capital Territory (FCT), Nigeria; NASENI Centre of Excellence in Nanotechnology and Advanced Materials, Km 4, Ondo Road, Akure, Ondo State, Nigeria; Department of Mechanical and Materials Engineering, Worcester Polytechnic Institute (WPI), 100 Institute Road, Worcester, MA, 01609, USA; Department of Biomedical Engineering, Worcester Polytechnic Institute, Gateway Park Life Sciences and Bioengineering Centre, 60 Prescott Street, Worcester, MA, 01609, USA
| | - Vanessa O Uzonwanne
- Department of Mechanical and Materials Engineering, Worcester Polytechnic Institute (WPI), 100 Institute Road, Worcester, MA, 01609, USA; Department of Biomedical Engineering, Worcester Polytechnic Institute, Gateway Park Life Sciences and Bioengineering Centre, 60 Prescott Street, Worcester, MA, 01609, USA
| | - Jonathan U A Madukwe
- Department of Histopathology, National Hospital, Abuja, Federal Capital Territory (FCT), Nigeria
| | - Said M Amin
- Department of Histopathology, National Hospital, Abuja, Federal Capital Territory (FCT), Nigeria
| | - Vitalis C Anye
- Department of Materials Science and Engineering, African University of Science and Technology, Km 10 Airport Road, Galadimawa, Abuja, Federal Capital Territory (FCT), Nigeria
| | - John D Obayemi
- Department of Mechanical and Materials Engineering, Worcester Polytechnic Institute (WPI), 100 Institute Road, Worcester, MA, 01609, USA; Department of Biomedical Engineering, Worcester Polytechnic Institute, Gateway Park Life Sciences and Bioengineering Centre, 60 Prescott Street, Worcester, MA, 01609, USA
| | - Olushola S Odusanya
- Department of Materials Science and Engineering, African University of Science and Technology, Km 10 Airport Road, Galadimawa, Abuja, Federal Capital Territory (FCT), Nigeria; Biotechnology and Genetic Engineering Advanced Laboratory, Sheda Science and Technology Complex (SHESTCO), Kwale, Abuja, Federal Capital Territory, Nigeria
| | - Winston O Soboyejo
- Department of Materials Science and Engineering, African University of Science and Technology, Km 10 Airport Road, Galadimawa, Abuja, Federal Capital Territory (FCT), Nigeria; Department of Mechanical and Materials Engineering, Worcester Polytechnic Institute (WPI), 100 Institute Road, Worcester, MA, 01609, USA; Department of Biomedical Engineering, Worcester Polytechnic Institute, Gateway Park Life Sciences and Bioengineering Centre, 60 Prescott Street, Worcester, MA, 01609, USA.
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3
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Singer CF, for the ABCSG, Holst F, Steurer S, Burandt EC, Lax SF, Jakesz R, Rudas M, Stöger H, Greil R, for the ABCSG, Sauter G, Filipits M, for the ABCSG, Simon R, Gnant M, for the ABCSG. Estrogen Receptor Alpha Gene Amplification Is an Independent Predictor of Long-Term Outcome in Postmenopausal Patients with Endocrine-Responsive Early Breast Cancer. Clin Cancer Res 2022; 28:4112-4120. [PMID: 35920686 PMCID: PMC9475247 DOI: 10.1158/1078-0432.ccr-21-4328] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 03/07/2022] [Accepted: 07/08/2022] [Indexed: 01/07/2023]
Abstract
PURPOSE Estrogen receptor (ER) expression is a prognostic parameter in breast cancer, and a prerequisite for the use of endocrine therapy. In ER+ early breast cancer, however, no receptor-associated biomarker exists that identifies patients with a particularly favorable outcome. We have investigated the value of ESR1 amplification in predicting the long-term clinical outcome in tamoxifen-treated postmenopausal women with endocrine-responsive breast cancer. EXPERIMENTAL DESIGN 394 patients who had been randomized into the tamoxifen-only arm of the prospective randomized ABCSG-06 trial of adjuvant endocrine therapy with available formalin-fixed, paraffin-embedded tumor tissue were included in this analysis. IHC ERα expression was evaluated both locally and in a central lab using the Allred score, while ESR1 gene amplification was evaluated by FISH analysis using the ESR1/CEP6 ratio indicating focal copy number alterations. RESULTS Focal ESR1 copy-number elevations (amplifications) were detected in 187 of 394 (47%) tumor specimens, and were associated with a favorable outcome: After a median follow-up of 10 years, women with intratumoral focal ESR1 amplification had a significantly longer distant recurrence-free survival [adjusted HR, 0.48; 95% confidence interval (CI), 0.26-0.91; P = 0.02] and breast cancer-specific survival (adjusted HR 0.47; 95% CI, 0.27-0.80; P = 0.01) as compared with women without ESR1 amplification. IHC ERα protein expression, evaluated by Allred score, correlated significantly with focal ESR1 amplification (P < 0.0001; χ2 test), but was not prognostic by itself. CONCLUSIONS Focal ESR1 amplification is an independent and powerful predictor for long-term distant recurrence-free and breast cancer-specific survival in postmenopausal women with endocrine-responsive early-stage breast cancer who received tamoxifen for 5 years.
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Affiliation(s)
- Christian F. Singer
- Department of OB/GYN, Medical University of Vienna, Vienna, Austria.,Corresponding Author: Christian F. Singer, Medical University of Vienna, AKH Wien, Waehringer Guertel 18-20, Vienna 1090, Austria. Phone: 4314-0400-28010, Fax: 4314-0400-23230; E-mail:
| | | | - Frederik Holst
- Department of OB/GYN, Medical University of Vienna, Vienna, Austria.,Department of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Stefan Steurer
- Department of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Eike C. Burandt
- Department of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sigurd F. Lax
- Department of Pathology, Medical University of Graz, Graz, Austria.,Hospital Graz II, Graz, Austria.,Johannes Kepler University, School of Medicine, Graz, Austria
| | - Raimund Jakesz
- Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - Margaretha Rudas
- Department of Pathology, Medical University of Vienna, Vienna, Austria
| | - Herbert Stöger
- Department of Medicine, Medical University of Graz, Graz, Austria
| | - Richard Greil
- Salzburg Cancer Research Institute - Center for Clinical and Immunology Trials and Cancer Cluster Salzburg; IIIrd Medical Department, Paracelsus Medical University Salzburg, Salzburg, Austria
| | | | - Guido Sauter
- Department of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Martin Filipits
- Center for Cancer Research, Medical University of Vienna, Vienna, Austria
| | | | - Ronald Simon
- Department of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Michael Gnant
- Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
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Porras L, Ismail H, Mader S. Positive Regulation of Estrogen Receptor Alpha in Breast Tumorigenesis. Cells 2021; 10:cells10112966. [PMID: 34831189 PMCID: PMC8616513 DOI: 10.3390/cells10112966] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 10/23/2021] [Accepted: 10/24/2021] [Indexed: 12/31/2022] Open
Abstract
Estrogen receptor alpha (ERα, NR3A1) contributes through its expression in different tissues to a spectrum of physiological processes, including reproductive system development and physiology, bone mass maintenance, as well as cardiovascular and central nervous system functions. It is also one of the main drivers of tumorigenesis in breast and uterine cancer and can be targeted by several types of hormonal therapies. ERα is expressed in a subset of luminal cells corresponding to less than 10% of normal mammary epithelial cells and in over 70% of breast tumors (ER+ tumors), but the basis for its selective expression in normal or cancer tissues remains incompletely understood. The mapping of alternative promoters and regulatory elements has delineated the complex genomic structure of the ESR1 gene and shed light on the mechanistic basis for the tissue-specific regulation of ESR1 expression. However, much remains to be uncovered to better understand how ESR1 expression is regulated in breast cancer. This review recapitulates the current body of knowledge on the structure of the ESR1 gene and the complex mechanisms controlling its expression in breast tumors. In particular, we discuss the impact of genetic alterations, chromatin modifications, and enhanced expression of other luminal transcription regulators on ESR1 expression in tumor cells.
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Hernando C, Ortega-Morillo B, Tapia M, Moragón S, Martínez MT, Eroles P, Garrido-Cano I, Adam-Artigues A, Lluch A, Bermejo B, Cejalvo JM. Oral Selective Estrogen Receptor Degraders (SERDs) as a Novel Breast Cancer Therapy: Present and Future from a Clinical Perspective. Int J Mol Sci 2021; 22:ijms22157812. [PMID: 34360578 PMCID: PMC8345926 DOI: 10.3390/ijms22157812] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 07/15/2021] [Accepted: 07/19/2021] [Indexed: 01/21/2023] Open
Abstract
Estrogen receptor-positive (ER+) is the most common subtype of breast cancer. Endocrine therapy is the fundamental treatment against this entity, by directly or indirectly modifying estrogen production. Recent advances in novel compounds, such as cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), or phosphoinositide 3-kinase (PI3K) inhibitors have improved progression-free survival and overall survival in these patients. However, some patients still develop endocrine resistance after or during endocrine treatment. Different underlying mechanisms have been identified as responsible for endocrine treatment resistance, where ESR1 gene mutations are one of the most studied, outstanding from others such as somatic alterations, microenvironment involvement and epigenetic changes. In this scenario, selective estrogen receptor degraders/downregulators (SERD) are one of the weapons currently in research and development against aromatase inhibitor- or tamoxifen-resistance. The first SERD to be developed and approved for ER+ breast cancer was fulvestrant, demonstrating also interesting activity in ESR1 mutated patients in the second line treatment setting. Recent investigational advances have allowed the development of new oral bioavailable SERDs. This review describes the evolution and ongoing studies in SERDs and new molecules against ER, with the hope that these novel drugs may improve our patients’ future landscape.
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Affiliation(s)
- Cristina Hernando
- Hospital Clínico de València, Instituto de Investigación INCLIVA, 46010 Valencia, Spain; (B.O.-M.); (M.T.); (S.M.); (M.T.M.); (I.G.-C.); (A.A.-A.); (A.L.); (B.B.)
- Correspondence: (C.H.); (J.M.C.)
| | - Belén Ortega-Morillo
- Hospital Clínico de València, Instituto de Investigación INCLIVA, 46010 Valencia, Spain; (B.O.-M.); (M.T.); (S.M.); (M.T.M.); (I.G.-C.); (A.A.-A.); (A.L.); (B.B.)
| | - Marta Tapia
- Hospital Clínico de València, Instituto de Investigación INCLIVA, 46010 Valencia, Spain; (B.O.-M.); (M.T.); (S.M.); (M.T.M.); (I.G.-C.); (A.A.-A.); (A.L.); (B.B.)
| | - Santiago Moragón
- Hospital Clínico de València, Instituto de Investigación INCLIVA, 46010 Valencia, Spain; (B.O.-M.); (M.T.); (S.M.); (M.T.M.); (I.G.-C.); (A.A.-A.); (A.L.); (B.B.)
| | - María Teresa Martínez
- Hospital Clínico de València, Instituto de Investigación INCLIVA, 46010 Valencia, Spain; (B.O.-M.); (M.T.); (S.M.); (M.T.M.); (I.G.-C.); (A.A.-A.); (A.L.); (B.B.)
| | - Pilar Eroles
- Hospital Clínico de València, Instituto de Investigación INCLIVA, 46010 Valencia, Spain; (B.O.-M.); (M.T.); (S.M.); (M.T.M.); (I.G.-C.); (A.A.-A.); (A.L.); (B.B.)
- Centro de Investigación Biomédica en Red de Oncología, CIBERONC-ISCIII, 28029 Madrid, Spain
- Departamento de Fisiología, Universidad de València, 46010 Valencia, Spain
| | - Iris Garrido-Cano
- Hospital Clínico de València, Instituto de Investigación INCLIVA, 46010 Valencia, Spain; (B.O.-M.); (M.T.); (S.M.); (M.T.M.); (I.G.-C.); (A.A.-A.); (A.L.); (B.B.)
| | - Anna Adam-Artigues
- Hospital Clínico de València, Instituto de Investigación INCLIVA, 46010 Valencia, Spain; (B.O.-M.); (M.T.); (S.M.); (M.T.M.); (I.G.-C.); (A.A.-A.); (A.L.); (B.B.)
| | - Ana Lluch
- Hospital Clínico de València, Instituto de Investigación INCLIVA, 46010 Valencia, Spain; (B.O.-M.); (M.T.); (S.M.); (M.T.M.); (I.G.-C.); (A.A.-A.); (A.L.); (B.B.)
- Centro de Investigación Biomédica en Red de Oncología, CIBERONC-ISCIII, 28029 Madrid, Spain
| | - Begoña Bermejo
- Hospital Clínico de València, Instituto de Investigación INCLIVA, 46010 Valencia, Spain; (B.O.-M.); (M.T.); (S.M.); (M.T.M.); (I.G.-C.); (A.A.-A.); (A.L.); (B.B.)
- Centro de Investigación Biomédica en Red de Oncología, CIBERONC-ISCIII, 28029 Madrid, Spain
| | - Juan Miguel Cejalvo
- Hospital Clínico de València, Instituto de Investigación INCLIVA, 46010 Valencia, Spain; (B.O.-M.); (M.T.); (S.M.); (M.T.M.); (I.G.-C.); (A.A.-A.); (A.L.); (B.B.)
- Centro de Investigación Biomédica en Red de Oncología, CIBERONC-ISCIII, 28029 Madrid, Spain
- Correspondence: (C.H.); (J.M.C.)
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Lee N, Park MJ, Song W, Jeon K, Jeong S. Currently Applied Molecular Assays for Identifying ESR1 Mutations in Patients with Advanced Breast Cancer. Int J Mol Sci 2020; 21:ijms21228807. [PMID: 33233830 PMCID: PMC7699999 DOI: 10.3390/ijms21228807] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 11/17/2020] [Accepted: 11/19/2020] [Indexed: 12/11/2022] Open
Abstract
Approximately 70% of breast cancers, the leading cause of cancer-related mortality worldwide, are positive for the estrogen receptor (ER). Treatment of patients with luminal subtypes is mainly based on endocrine therapy. However, ER positivity is reduced and ESR1 mutations play an important role in resistance to endocrine therapy, leading to advanced breast cancer. Various methodologies for the detection of ESR1 mutations have been developed, and the most commonly used method is next-generation sequencing (NGS)-based assays (50.0%) followed by droplet digital PCR (ddPCR) (45.5%). Regarding the sample type, tissue (50.0%) was more frequently used than plasma (27.3%). However, plasma (46.2%) became the most used method in 2016-2019, in contrast to 2012-2015 (22.2%). In 2016-2019, ddPCR (61.5%), rather than NGS (30.8%), became a more popular method than it was in 2012-2015. The easy accessibility, non-invasiveness, and demonstrated usefulness with high sensitivity of ddPCR using plasma have changed the trends. When using these assays, there should be a comprehensive understanding of the principles, advantages, vulnerability, and precautions for interpretation. In the future, advanced NGS platforms and modified ddPCR will benefit patients by facilitating treatment decisions efficiently based on information regarding ESR1 mutations.
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Affiliation(s)
- Nuri Lee
- Department of Laboratory Medicine, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul 07440, Korea; (N.L.); (M.-J.P.); (W.S.)
| | - Min-Jeong Park
- Department of Laboratory Medicine, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul 07440, Korea; (N.L.); (M.-J.P.); (W.S.)
| | - Wonkeun Song
- Department of Laboratory Medicine, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul 07440, Korea; (N.L.); (M.-J.P.); (W.S.)
| | - Kibum Jeon
- Department of Laboratory Medicine, Hangang Sacred Heart Hospital, Hallym University College of Medicine, Seoul 07440, Korea;
| | - Seri Jeong
- Department of Laboratory Medicine, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul 07440, Korea; (N.L.); (M.-J.P.); (W.S.)
- Correspondence: ; Tel.: +82-845-5305
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Rodriguez D, Ramkairsingh M, Lin X, Kapoor A, Major P, Tang D. The Central Contributions of Breast Cancer Stem Cells in Developing Resistance to Endocrine Therapy in Estrogen Receptor (ER)-Positive Breast Cancer. Cancers (Basel) 2019; 11:cancers11071028. [PMID: 31336602 PMCID: PMC6678134 DOI: 10.3390/cancers11071028] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2019] [Revised: 07/17/2019] [Accepted: 07/17/2019] [Indexed: 12/11/2022] Open
Abstract
Breast cancer stem cells (BCSC) play critical roles in the acquisition of resistance to endocrine therapy in estrogen receptor (ER)-positive (ER + ve) breast cancer (BC). The resistance results from complex alterations involving ER, growth factor receptors, NOTCH, Wnt/β-catenin, hedgehog, YAP/TAZ, and the tumor microenvironment. These mechanisms are likely converged on regulating BCSCs, which then drive the development of endocrine therapy resistance. In this regard, hormone therapies enrich BCSCs in ER + ve BCs under both pre-clinical and clinical settings along with upregulation of the core components of “stemness” transcriptional factors including SOX2, NANOG, and OCT4. SOX2 initiates a set of reactions involving SOX9, Wnt, FXY3D, and Src tyrosine kinase; these reactions stimulate BCSCs and contribute to endocrine resistance. The central contributions of BCSCs to endocrine resistance regulated by complex mechanisms offer a unified strategy to counter the resistance. ER + ve BCs constitute approximately 75% of BCs to which hormone therapy is the major therapeutic approach. Likewise, resistance to endocrine therapy remains the major challenge in the management of patients with ER + ve BC. In this review we will discuss evidence supporting a central role of BCSCs in developing endocrine resistance and outline the strategy of targeting BCSCs to reduce hormone therapy resistance.
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Affiliation(s)
- David Rodriguez
- Department of Medicine, McMaster University, Hamilton, ON L8S 4K1, Canada
- The Research Institute of St Joe's Hamilton, St Joseph's Hospital, Hamilton, ON L8N 4A6, Canada
- Urological Cancer Center for Research and Innovation (UCCRI), St Joseph's Hospital, Hamilton, ON L8N 4A6, Canada
- The Hamilton Center for Kidney Research, St. Joseph's Hospital, Hamilton, ON L8N 4A6, Canada
| | - Marc Ramkairsingh
- Department of Medicine, McMaster University, Hamilton, ON L8S 4K1, Canada
- The Research Institute of St Joe's Hamilton, St Joseph's Hospital, Hamilton, ON L8N 4A6, Canada
- Urological Cancer Center for Research and Innovation (UCCRI), St Joseph's Hospital, Hamilton, ON L8N 4A6, Canada
- The Hamilton Center for Kidney Research, St. Joseph's Hospital, Hamilton, ON L8N 4A6, Canada
| | - Xiaozeng Lin
- Department of Medicine, McMaster University, Hamilton, ON L8S 4K1, Canada
- The Research Institute of St Joe's Hamilton, St Joseph's Hospital, Hamilton, ON L8N 4A6, Canada
- Urological Cancer Center for Research and Innovation (UCCRI), St Joseph's Hospital, Hamilton, ON L8N 4A6, Canada
- The Hamilton Center for Kidney Research, St. Joseph's Hospital, Hamilton, ON L8N 4A6, Canada
| | - Anil Kapoor
- The Research Institute of St Joe's Hamilton, St Joseph's Hospital, Hamilton, ON L8N 4A6, Canada
- Urological Cancer Center for Research and Innovation (UCCRI), St Joseph's Hospital, Hamilton, ON L8N 4A6, Canada
- Department of Surgery, McMaster University, Hamilton, Hamilton, ON L8S 4K1, Canada
| | - Pierre Major
- Division of Medical Oncology, Department of Oncology, McMaster University, Hamilton, ON, L8V 5C2, Canada
| | - Damu Tang
- Department of Medicine, McMaster University, Hamilton, ON L8S 4K1, Canada.
- The Research Institute of St Joe's Hamilton, St Joseph's Hospital, Hamilton, ON L8N 4A6, Canada.
- Urological Cancer Center for Research and Innovation (UCCRI), St Joseph's Hospital, Hamilton, ON L8N 4A6, Canada.
- The Hamilton Center for Kidney Research, St. Joseph's Hospital, Hamilton, ON L8N 4A6, Canada.
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8
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Lei JT, Gou X, Seker S, Ellis MJ. ESR1 alterations and metastasis in estrogen receptor positive breast cancer. ACTA ACUST UNITED AC 2019; 5. [PMID: 31106278 PMCID: PMC6519472 DOI: 10.20517/2394-4722.2019.12] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Endocrine therapy is essential for the treatment of patients with estrogen receptor positive (ER+) breast cancer, however, resistance and the development of metastatic disease is common. Understanding how ER+ breast cancer metastasizes is critical since the major cause of death in breast cancer is metastasis to distant organs. Results from many studies suggest dysregulation of the estrogen receptor alpha gene (ESR1 ) contributes to therapeutic resistance and metastatic biology. This review covers both pre-clinical and clinical evidence on the spectrum of ESR1 alterations including amplification, point mutations, and genomic rearrangement events driving treatment resistance and metastatic potential of ER+ breast cancer. Importantly, we describe how these ESR1 alterations may provide therapeutic opportunities to improve outcomes in patients with lethal, metastatic breast cancer.
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Affiliation(s)
- Jonathan T Lei
- Interdepartmental Graduate Program in Translational Biology & Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, USA.,Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Xuxu Gou
- Interdepartmental Graduate Program in Translational Biology & Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, USA.,Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Sinem Seker
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Matthew J Ellis
- Interdepartmental Graduate Program in Translational Biology & Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, USA.,Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.,Departments of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
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9
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Basudan A, Priedigkeit N, Hartmaier RJ, Sokol ES, Bahreini A, Watters RJ, Boisen MM, Bhargava R, Weiss KR, Karsten MM, Denkert C, Blohmer JU, Leone JP, Hamilton RL, Brufsky AM, Elishaev E, Lucas PC, Lee AV, Oesterreich S. Frequent ESR1 and CDK Pathway Copy-Number Alterations in Metastatic Breast Cancer. Mol Cancer Res 2019; 17:457-468. [PMID: 30355675 PMCID: PMC6359977 DOI: 10.1158/1541-7786.mcr-18-0946] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Revised: 10/04/2018] [Accepted: 10/11/2018] [Indexed: 12/30/2022]
Abstract
DNA sequencing has identified a limited number of driver mutations in metastatic breast cancer beyond single base-pair mutations in the estrogen receptor (ESR1). However, our previous studies and others have observed that structural variants, such as ESR1 fusions, may also play a role. Therefore, we expanded upon these observations by performing a comprehensive and highly sensitive characterization of copy-number (CN) alterations in a large clinical cohort of metastatic specimens. NanoString DNA hybridization was utilized to measure CN gains, amplifications, and deletions of 67 genes in 108 breast cancer metastases, and in 26 cases, the patient-matched primary tumor. For ESR1, a copyshift algorithm was applied to identify CN imbalances at exon-specific resolution and queried large data sets (>15,000 tumors) that had previously undergone next-generation sequencing (NGS). Interestingly, a subset of ER+ tumors showed increased ESR1 CN (11/82, 13%); three had CN amplifications (4%) and eight had gains (10%). Increased ESR1 CN was enriched in metastatic specimens versus primary tumors, and this was orthogonally confirmed in a large NGS data set. ESR1-amplified tumors showed a site-specific enrichment for bone metastases and worse outcomes than nonamplified tumors. No ESR1 CN amplifications and only one gain was identified in ER- tumors. ESR1 copyshift was present in 5 of the 11 ESR1-amplified tumors. Other frequent amplifications included ERBB2, GRB7, and cell-cycle pathway members CCND1 and CDK4/6, which showed mutually exclusivity with deletions of CDKN2A, CDKN2B, and CDKN1B. IMPLICATIONS: Copy-number alterations of ESR1 and key CDK pathway genes are frequent in metastatic breast cancers, and their clinical relevance should be tested further.
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Affiliation(s)
- Ahmed Basudan
- Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania
- Women's Cancer Research Center, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania
- Department of Clinical Lab Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Nolan Priedigkeit
- Women's Cancer Research Center, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania
- School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Ryan J Hartmaier
- Women's Cancer Research Center, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania
| | | | - Amir Bahreini
- Women's Cancer Research Center, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Rebecca J Watters
- Department of Orthopedic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Michelle M Boisen
- Women's Cancer Research Center, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania
- Department of Obstetrics and Gynecology, University of Pittsburgh, Pittsburgh, Pennsylvania
- Magee-Women Hospital, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Rohit Bhargava
- Women's Cancer Research Center, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania
- Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Kurt R Weiss
- Department of Orthopedic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania
- Department of Surgical Oncology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | | | | | | | - Jose P Leone
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Ronald L Hamilton
- Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Adam M Brufsky
- Women's Cancer Research Center, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania
- Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Esther Elishaev
- Women's Cancer Research Center, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania
- Magee-Women Hospital, University of Pittsburgh, Pittsburgh, Pennsylvania
- Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Peter C Lucas
- Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Adrian V Lee
- Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania
- Women's Cancer Research Center, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Steffi Oesterreich
- Women's Cancer Research Center, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania.
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania
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10
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Martínez-Pérez C, Turnbull AK, Dixon JM. The evolving role of receptors as predictive biomarkers for metastatic breast cancer. Expert Rev Anticancer Ther 2018; 19:121-138. [PMID: 30501540 DOI: 10.1080/14737140.2019.1552138] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
INTRODUCTION In breast cancer, estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) are essential biomarkers to predict response to endocrine and anti-HER2 therapies, respectively. In metastatic breast cancer, the use of these receptors and targeted therapies present additional challenges: temporal heterogeneity, together with limited sampling methodologies, hinders receptor status assessment, and the constant evolution of the disease invariably leads to resistance to treatment. Areas covered: This review summarizes the genomic abnormalities in ER and HER2, such as mutations, amplifications, translocations, and alternative splicing, emerging as novel biomarkers that provide an insight into underlying mechanisms of resistance and hold potential predictive value to inform treatment selection. We also describe how liquid biopsies for sampling of circulating markers and ultrasensitive detection technologies have emerged which complement ongoing efforts for biomarker discovery and analysis. Expert commentary: While evidence suggests that genomic aberrations in ER and HER2 could contribute to meeting the pressing need for better predictive biomarkers, efforts need to be made to standardize assessment methods and better understand the resistance mechanisms these markers denote. Taking advantage of emerging technologies, research in upcoming years should include prospective trials incorporating these predictors into the study design to validate their potential clinical value.
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Affiliation(s)
- Carlos Martínez-Pérez
- a Breast Cancer Now Edinburgh Team, Institute of Genetics and Molecular Medicine , University of Edinburgh, Western General Hospital , Edinburgh , UK
| | - Arran K Turnbull
- a Breast Cancer Now Edinburgh Team, Institute of Genetics and Molecular Medicine , University of Edinburgh, Western General Hospital , Edinburgh , UK
| | - J Michael Dixon
- a Breast Cancer Now Edinburgh Team, Institute of Genetics and Molecular Medicine , University of Edinburgh, Western General Hospital , Edinburgh , UK.,b Edinburgh Breast Unit , Western General Hospital , Edinburgh , UK
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11
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Szostakowska M, Trębińska-Stryjewska A, Grzybowska EA, Fabisiewicz A. Resistance to endocrine therapy in breast cancer: molecular mechanisms and future goals. Breast Cancer Res Treat 2018; 173:489-497. [PMID: 30382472 PMCID: PMC6394602 DOI: 10.1007/s10549-018-5023-4] [Citation(s) in RCA: 126] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Accepted: 10/20/2018] [Indexed: 02/06/2023]
Abstract
Introduction The majority of breast cancers (BCs) are characterized by the expression of estrogen receptor alpha (ERα+). ERα acts as ligand-dependent transcription factor for genes associated with cell survival, proliferation, and tumor growth. Thus, blocking the estrogen agonist effect on ERα is the main strategy in the treatment of ERα+ BCs. However, despite the development of targeted anti-estrogen therapies for ER+ BC, around 30–50% of early breast cancer patients will relapse. Acquired resistance to endocrine therapy is a great challenge in ER+ BC patient treatment. Discussion Anti-estrogen resistance is a consequence of molecular changes, which allow for tumor growth irrespective of estrogen presence. Those changes may be associated with ERα modifications either at the genetic, regulatory or protein level. Additionally, the activation of alternate growth pathways and/or cell survival mechanisms can lead to estrogen-independence and endocrine resistance. Conclusion This comprehensive review summarizes molecular mechanisms associated with resistance to anti-estrogen therapy, focusing on genetic alterations, stress responses, cell survival mechanisms, and cell reprogramming.
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Affiliation(s)
- Małgorzata Szostakowska
- Department of Molecular and Translational Oncology, The Maria Skłodowska-Curie Institute of Oncology, Roentgena 5, Warsaw, Poland
| | - Alicja Trębińska-Stryjewska
- Department of Molecular and Translational Oncology, The Maria Skłodowska-Curie Institute of Oncology, Roentgena 5, Warsaw, Poland
| | - Ewa Anna Grzybowska
- Department of Molecular and Translational Oncology, The Maria Skłodowska-Curie Institute of Oncology, Roentgena 5, Warsaw, Poland
| | - Anna Fabisiewicz
- Department of Molecular and Translational Oncology, The Maria Skłodowska-Curie Institute of Oncology, Roentgena 5, Warsaw, Poland.
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12
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Pejerrey SM, Dustin D, Kim JA, Gu G, Rechoum Y, Fuqua SAW. The Impact of ESR1 Mutations on the Treatment of Metastatic Breast Cancer. Discov Oncol 2018; 9:215-228. [PMID: 29736566 DOI: 10.1007/s12672-017-0306-5] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2017] [Accepted: 08/31/2017] [Indexed: 12/25/2022] Open
Abstract
After nearly 20 years of research, it is now established that mutations within the estrogen receptor (ER) gene, ESR1, frequently occur in metastatic breast cancer and influence response to hormone therapy. Though early studies presented differing results, sensitive sequencing techniques now show that ESR1 mutations occur at a frequency between 20 and 40% depending on the assay method. Recent studies have focused on several "hot spot mutations," a cluster of mutations found in the hormone-binding domain of the ESR1 gene. Throughout the course of treatment, tumor evolution can occur, and ESR1 mutations emerge and become enriched in the metastatic setting. Sensitive techniques to continually monitor mutant burden in vivo are needed to effectively treat patients with mutant ESR1. The full impact of these mutations on tumor response to different therapies remains to be determined. However, recent studies indicate that mutant-bearing tumors may be less responsive to specific hormonal therapies, and suggest that aromatase inhibitor (AI) therapy may select for the emergence of ESR1 mutations. Additionally, different mutations may respond discretely to targeted therapies. The need for more preclinical mechanistic studies on ESR1 mutations and the development of better agents to target these mutations are urgently needed. In the future, sequential monitoring of ESR1 mutational status will likely direct personalized therapeutic regimens appropriate to each tumor's unique mutational landscape.
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Affiliation(s)
- Sasha M Pejerrey
- Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, MS: 600, Houston, TX, 77030, USA
| | - Derek Dustin
- Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, MS: 600, Houston, TX, 77030, USA
| | - Jin-Ah Kim
- Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, MS: 600, Houston, TX, 77030, USA
| | - Guowei Gu
- Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, MS: 600, Houston, TX, 77030, USA
| | - Yassine Rechoum
- Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, MS: 600, Houston, TX, 77030, USA
| | - Suzanne A W Fuqua
- Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, MS: 600, Houston, TX, 77030, USA.
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13
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Azarnezhad A, Tabrizi M, Atri M, Mehdipour P. ESR1 gene amplification in an Iranian population with early onset invasive ductal breast carcinoma. BREAST CANCER MANAGEMENT 2018. [DOI: 10.2217/bmt-2017-0018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aim: The study aimed to evaluate a modified SYBR Green qPCR method to study the inter-relations of ESR1 amplification to other parameters including ER expression status, clinicopathological features and responsiveness to tamoxifen. Materials & methods: 35 breast cancer tissues were assessed for ESR1 amplification by a modified qPCR. Results: Amplification of ESR1 was observed in 31.4% out of 35 samples. ESR1 amplification and overexpression were significantly correlated (Spearman's Rho = 0.658; p < 0.001). ESR1 amplification was also statistically associated with positive response to tamoxifen (p = 0.0005), lower tumor grade (p = 0.027) and lower tumor stage (p = 0.005). Conclusion: Findings showed a positive correlation between ER amplification and ER-α expression and highlighted the potential clinical value of using SYBR Green qPCR to quantify amplification of ESR1. ESR1 amplification could be used as an indicator of positive response to tamoxifen and might have a clinicopathological significance. However, the qPCR data should be confirmed by fluorescence in situ hybridization.
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Affiliation(s)
- Asaad Azarnezhad
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mina Tabrizi
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Morteza Atri
- Department of Surgery, Cancer Institute, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Parvin Mehdipour
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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14
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Bailey SD, Desai K, Kron KJ, Mazrooei P, Sinnott-Armstrong NA, Treloar AE, Dowar M, Thu KL, Cescon DW, Silvester J, Yang SYC, Wu X, Pezo RC, Haibe-Kains B, Mak TW, Bedard PL, Pugh TJ, Sallari RC, Lupien M. Noncoding somatic and inherited single-nucleotide variants converge to promote ESR1 expression in breast cancer. Nat Genet 2016; 48:1260-6. [PMID: 27571262 PMCID: PMC5042848 DOI: 10.1038/ng.3650] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2015] [Accepted: 07/26/2016] [Indexed: 12/18/2022]
Abstract
Sustained expression of the oestrogen receptor alpha (ESR1) drives two-thirds of breast cancer and defines the ESR1-positive subtype. ESR1 engages enhancers upon oestrogen stimulation to establish an oncogenic expression program1. Somatic copy number alterations involving the ESR1 gene occur in approximately 1% of ESR1-positive breast cancers2–5, implying that other mechanisms underlie the persistent expression of ESR1. We report the significant enrichment of somatic mutations within the set of regulatory elements (SRE) regulating ESR1 in 7% of ESR1-positive breast cancers. These mutations regulate ESR1 expression by modulating transcription factor binding to the DNA. The SRE includes a recurrently mutated enhancer whose activity is also affected by a functional inherited single nucleotide variant (SNV) rs9383590 that accounts for several breast cancer risk-loci. Our work highlights the importance of considering the combinatorial activity of regulatory elements as a single unit to delineate the impact of noncoding genetic alterations on single genes in cancer.
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Affiliation(s)
- Swneke D Bailey
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.,Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - Kinjal Desai
- Department of Genetics, Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, New Hampshire, USA
| | - Ken J Kron
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.,Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - Parisa Mazrooei
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.,Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | | | - Aislinn E Treloar
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.,Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - Mark Dowar
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Kelsie L Thu
- Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - David W Cescon
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.,Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Jennifer Silvester
- Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - S Y Cindy Yang
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.,Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - Xue Wu
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Rossanna C Pezo
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Benjamin Haibe-Kains
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.,Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.,Department of Computer Science, University of Toronto, Toronto, Ontario, Canada
| | - Tak W Mak
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.,Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Philippe L Bedard
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.,Division of Medical Oncology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Trevor J Pugh
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.,Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - Richard C Sallari
- Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA
| | - Mathieu Lupien
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.,Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.,Ontario Institute for Cancer Research, Toronto, Ontario, Canada
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15
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Holst F. Estrogen receptor alpha gene amplification in breast cancer: 25 years of debate. World J Clin Oncol 2016; 7:160-173. [PMID: 27081639 PMCID: PMC4826962 DOI: 10.5306/wjco.v7.i2.160] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Revised: 01/05/2016] [Accepted: 02/16/2016] [Indexed: 02/06/2023] Open
Abstract
Twenty-five years ago, Nembrot and colleagues reported amplification of the estrogen receptor alpha gene (ESR1) in breast cancer, initiating a broad and still ongoing scientific debate on the prevalence and clinical significance of this genetic aberration, which affects one of the most important genes in breast cancer. Since then, a multitude of studies on this topic has been published, covering a wide range of divergent results and arguments. The reported prevalence of this alteration in breast cancer ranges from 0% to 75%, suggesting that ESR1 copy number analysis is hampered by technical and interpreter issues. To date, two major issues related to ESR1 amplification remain to be conclusively addressed: (1) The extent to which abundant amounts of messenger RNA can mimic amplification in standard fluorescence in situ hybridization assays in the analysis of strongly expressed genes like ESR1, and (2) the clinical relevance of ESR1 amplification: Such relevance is strongly disputed, with data showing predictive value for response as well as for resistance of the cancer to anti-estrogen therapies, or for subsequent development of cancers in the case of precursor lesions that display amplification of ESR1. This review provides a comprehensive summary of the various views on ESR1 amplification, and highlights explanations for the contradictions and conflicting data that could inform future ESR1 research.
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16
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Irish JC, Mills JN, Turner-Ivey B, Wilson RC, Guest ST, Rutkovsky A, Dombkowski A, Kappler CS, Hardiman G, Ethier SP. Amplification of WHSC1L1 regulates expression and estrogen-independent activation of ERα in SUM-44 breast cancer cells and is associated with ERα over-expression in breast cancer. Mol Oncol 2016; 10:850-65. [PMID: 27005559 PMCID: PMC4920706 DOI: 10.1016/j.molonc.2016.02.003] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Revised: 02/17/2016] [Accepted: 02/18/2016] [Indexed: 11/29/2022] Open
Abstract
The 8p11‐p12 amplicon occurs in approximately 15% of breast cancers in aggressive luminal B‐type tumors. Previously, we identified WHSC1L1 as a driving oncogene from this region. Here, we demonstrate that over‐expression of WHSC1L1 is linked to over‐expression of ERα in SUM‐44 breast cancer cells and in primary human breast cancers. Knock‐down of WHSC1L1, particularly WHSC1L1‐short, had a dramatic effect on ESR1 mRNA and ERα protein levels. SUM‐44 cells do not require exogenous estrogen for growth in vitro; however, they are dependent on ERα expression, as ESR1 knock‐down or exposure to the selective estrogen receptor degrader fulvestrant resulted in growth inhibition. ChIP‐Seq experiments utilizing ERα antibodies demonstrated extensive ERα binding to chromatin in SUM‐44 cells under estrogen‐free conditions. ERα bound to ERE and FOXA1 motifs under estrogen‐free conditions and regulated expression of estrogen‐responsive genes. Short‐term treatment with estradiol enhanced binding of ERα to chromatin and influenced expression of many of the same genes to which ERα was bound under estrogen‐free conditions. Finally, knock‐down of WHSC1L1 in SUM‐44 cells resulted in loss of ERα binding to chromatin under estrogen‐free conditions, which was restored upon exposure to estradiol. These results indicate the SUM‐44 cells are a good model of a subset of luminal B breast cancers that have the 8p11‐p12 amplicon, over‐express WHSC1L1, and over‐express ERα, but are independent of estrogen for binding to chromatin and regulation of gene expression. Breast cancers such as these, that are dependent on ERα activity but independent of estradiol, are a major cause of breast cancer mortality.
SUM44 is a model cell line for ERα positive breast cancer with the 8p11 amplicon. WHSC1L1 is a driving oncogene from the 8p11 amplicon in SUM44 cells. SUM44 breast cancer cells have high ERα expression, regulated by WHSC1L1 knockdown. ERα is required for growth and survival of SUM44 cells but is estrogen‐independent. WHSC1L1 knock‐down re‐sensitizes ERα to estradiol for binding to essential genes.
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Affiliation(s)
- Jonathan C Irish
- Department of Pathology and Laboratory Medicine, Hollings Cancer Center, 86 Jonathan Lucas St, Charleston, SC 29425, USA; Department of Cancer Biology, Wayne State University School of Medicine, 540 E Canfield St, Detroit, MI 48201, USA.
| | - Jamie N Mills
- Department of Pathology and Laboratory Medicine, Hollings Cancer Center, 86 Jonathan Lucas St, Charleston, SC 29425, USA.
| | - Brittany Turner-Ivey
- Department of Pathology and Laboratory Medicine, Hollings Cancer Center, 86 Jonathan Lucas St, Charleston, SC 29425, USA.
| | - Robert C Wilson
- Department of Pathology and Laboratory Medicine, Hollings Cancer Center, 86 Jonathan Lucas St, Charleston, SC 29425, USA.
| | - Stephen T Guest
- Department of Pathology and Laboratory Medicine, Hollings Cancer Center, 86 Jonathan Lucas St, Charleston, SC 29425, USA.
| | - Alexandria Rutkovsky
- Department of Pathology and Laboratory Medicine, Hollings Cancer Center, 86 Jonathan Lucas St, Charleston, SC 29425, USA.
| | - Alan Dombkowski
- Department of Cancer Biology, Wayne State University School of Medicine, 540 E Canfield St, Detroit, MI 48201, USA.
| | - Christiana S Kappler
- Department of Pathology and Laboratory Medicine, Hollings Cancer Center, 86 Jonathan Lucas St, Charleston, SC 29425, USA.
| | - Gary Hardiman
- Department of Medicine and Public Health, Medical University of South Carolina, 171 Ashley Ave, Charleston, SC 29425, USA.
| | - Stephen P Ethier
- Department of Pathology and Laboratory Medicine, Hollings Cancer Center, 86 Jonathan Lucas St, Charleston, SC 29425, USA.
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17
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Titloye NA, Foster A, Omoniyi-Esan GO, Komolafe AO, Daramola AO, Adeoye OA, Adisa AO, Manoharan A, Pathak D, D'Cruz MN, Alizadeh Y, Lewis PD, Shaaban AM. Histological Features and Tissue Microarray Taxonomy of Nigerian Breast Cancer Reveal Predominance of the High-Grade Triple-Negative Phenotype. Pathobiology 2016; 83:24-32. [PMID: 26730581 DOI: 10.1159/000441949] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Accepted: 10/26/2015] [Indexed: 11/19/2022] Open
Abstract
INTRODUCTION Little is known about the biology, molecular profile and hence optimal treatment of African Nigerian breast cancer. The aim of this work, therefore, was to characterize the histology and molecular profile of Nigerian breast cancer. METHODS Breast carcinomas from women at 6 centres of similar tribal origin in Nigeria were reviewed and assembled into tissue microarrays (TMAs), and sections were stained for hormone receptors, i.e. estrogen receptor (ER)α, ERβ1, ERβ progesterone receptor (PR) and androgen receptor, cyclin D, HER2, Ki67 and cytokeratins (CKs), i.e. CK5/6 and CK14 (basal) and CK18 and 19 (luminal). RESULTS A total of 835 tumours were analysed. The mean age at diagnosis was 48.62 ± 12.41 years. The most common histological subtype was ductal NST (no-special-type) carcinoma (87.3%). Over 90% of the tumours were grade 2 or 3. The predominant molecular phenotype was the non-basal, triple-negative type (47.65%) followed by the HER2-positive group (19.6%). The percentage of ER-, PR- and HER2-positive tumours was 22.4, 18.9 and 18.8%, respectively. CONCLUSION Nigerian breast cancer predominantly has a high-grade, triple-negative profile. It occurs at a younger age and bears similarities at the molecular level to pre-menopausal breast cancer in white women, with remarkably lower levels of ERβ expression. The early presentation and histological and molecular phenotype may explain the poor prognosis, and tailoring treatment strategies to target this unique profile are required.
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Affiliation(s)
- N A Titloye
- School of Medical Science, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
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18
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Ma CX, Bose R, Ellis MJ. Prognostic and Predictive Biomarkers of Endocrine Responsiveness for Estrogen Receptor Positive Breast Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 882:125-54. [PMID: 26987533 DOI: 10.1007/978-3-319-22909-6_5] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/03/2022]
Abstract
The estrogen-dependent nature of breast cancer is the fundamental basis for endocrine therapy. The presence of estrogen receptor (ER), the therapeutic target of endocrine therapy, is a prerequisite for this therapeutic approach. However, estrogen-independent growth often exists de novo at diagnosis or develops during the course of endocrine therapy. Therefore ER alone is insufficient in predicting endocrine therapy efficacy. Several RNA-based multigene assays are now available in clinical practice to assess distant recurrence risk, with majority of these assays evaluated in patients treated with 5 years of adjuvant endocrine therapy. While MammaPrint and Oncotype Dx are most predictive of recurrence risk within the first 5 years of diagnosis, Prosigna, Breast Cancer Index (BCI), and EndoPredict Clin have also demonstrated utility in predicting late recurrence. In addition, PAM50, or Prosigna, provides further biological insights by classifying breast cancers into intrinsic molecular subtypes. Additional strategies are under investigation in prospective clinical trials to differentiate endocrine sensitive and resistant tumors and include on-treatment Ki-67 and Preoperative Endocrine Prognostic Index (PEPI) score in the setting of neoadjuvant endocrine therapy. These biomarkers have become important tools in clinical practice for the identification of low risk patients for whom chemotherapy could be avoided. However, there is much work ahead toward the development of a molecular classification that informs the biology and novel therapeutic targets in high-risk disease as chemotherapy has only modest benefit in this population. The recognition of somatic mutations and their relationship to endocrine therapy responsiveness opens important opportunities toward this goal.
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Affiliation(s)
- Cynthia X Ma
- Division of Oncology, Department of Medicine, Siteman Cancer Center, Washington University School of Medicine, 660 South Euclid Avenue, 63110, St Louis, MO, USA
| | - Ron Bose
- Division of Oncology, Department of Medicine, Siteman Cancer Center, Washington University School of Medicine, 660 South Euclid Avenue, 63110, St Louis, MO, USA
| | - Matthew J Ellis
- Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, 320A Cullen, MS 600, 77030, Houston, TX, USA.
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Thomas C, Gustafsson JÅ. Estrogen receptor mutations and functional consequences for breast cancer. Trends Endocrinol Metab 2015; 26:467-76. [PMID: 26183887 DOI: 10.1016/j.tem.2015.06.007] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2015] [Revised: 06/23/2015] [Accepted: 06/23/2015] [Indexed: 02/07/2023]
Abstract
A significant number of estrogen receptor α (ERα)-positive breast tumors develop resistance to endocrine therapy and recur with metastatic disease. Several mechanisms of endocrine resistance have been proposed, including genetic alterations that lead to ERs with altered protein sequence. By altering the conformation of the protein and increasing the interaction with coactivators, point mutations in ESR1, the gene encoding ERα, promote an active form of the receptor in the absence of hormone that assists tumor cells to evade hormonal treatments. Recent studies have confirmed that ESR1 point mutations frequently occur in metastatic breast tumors that are refractory to endocrine therapy, and suggest the development of novel strategies that may be more effective in controlling ER signaling and benefit patients with recurrent and metastatic disease.
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Affiliation(s)
- Christoforos Thomas
- Department of Biology and Biochemistry, Center for Nuclear Receptors and Cell Signaling, University of Houston, 3605 Cullen Boulevard, Houston, TX 77204, USA.
| | - Jan-Åke Gustafsson
- Department of Biology and Biochemistry, Center for Nuclear Receptors and Cell Signaling, University of Houston, 3605 Cullen Boulevard, Houston, TX 77204, USA.
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20
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Status of estrogen receptor 1 (ESR1) gene in mastopathy predicts subsequent development of breast cancer. Breast Cancer Res Treat 2015; 151:709-15. [PMID: 25981900 DOI: 10.1007/s10549-015-3427-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2015] [Accepted: 05/11/2015] [Indexed: 10/23/2022]
Abstract
Mastopathy is a common disease of the breast likely associated with elevated estrogen levels and a putative risk factor for breast cancer. The role of estrogen receptor alpha (ESR1) in mastopathy has not been investigated previously. Here, we investigated the prevalence of ESR1 gene amplification in mastopathy and its prediction for breast cancer. Paraffin-embedded tissues from 58 women with invasive breast cancer were analyzed. For all women, tissues with mastopathy taken at least 1.5 years before first diagnosis of breast cancer were available. Tissue from 46 women with mastopathy without a diagnosis of breast carcinoma in the observed time frame (12-18 years) was used as control. Fluorescence in situ hybridization analysis revealed that ESR1 was amplified in nine of 58 (15.5 %) breast cancers. All ESR1-amplified breast cancers were strongly positive for estrogen receptor with ER immunohistochemistry. Interestingly, in women with ESR1 amplification in breast cancer, the amplification was detectable in mastopathic tissues prior to the first diagnosis of breast cancer but was absent in tissues from women with mastopathy who did not develop breast cancer. Our study suggests that ESR1 gene amplification is an early event in breast pathology and might be a helpful predictive marker to identify patients at high risk of developing breast cancer.
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Abstract
Oestrogen receptor-positive (ER(+)) breast cancer is a major cause of cancer death in women. Although aromatase inhibitors suppress the function of ER and reduce the risk of recurrence, therapeutic resistance is common and essentially inevitable in advanced disease. This Review considers both genomic and cell biological explanations as to why ER(+) breast cancer cells persist, progress and cause an incurable, lethal, systemic disease. The design and outcomes of clinical trials are considered with the perspective that resistance mechanisms are heterogeneous, and therefore biomarker and somatic mutation-based stratification and eligibility will be essential for improvements in patient outcomes.
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Affiliation(s)
- Cynthia X Ma
- Division of Oncology, Department of Medicine, Siteman Cancer Center, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA
| | - Tomás Reinert
- Department of Medical Oncology, Instituto Nacional de Câncer (INCA), Praça da Cruz Vermelha, 23, 20230-130, Rio de Janeiro, Brazil
| | - Izabela Chmielewska
- Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, Jaczewskiego 8 St., 20-954, Lublin, Poland
| | - Matthew J Ellis
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston 77030, Texas, USA
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22
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Chen JR, Hsieh TY, Chen HY, Yeh KY, Chen KS, ChangChien YC, Pintye M, Chang LC, Hwang CC, Chien HP, Hsu YC. Absence of estrogen receptor alpha (ESR1) gene amplification in a series of breast cancers in Taiwan. Virchows Arch 2014; 464:689-99. [PMID: 24756215 DOI: 10.1007/s00428-014-1576-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2014] [Revised: 03/18/2014] [Accepted: 03/21/2014] [Indexed: 11/28/2022]
Abstract
Immunohistochemical expression of ERα, encoded by the ESR1 (estrogen receptor 1) gene located at 6q25.1, is the most important determinant of responsiveness to endocrine therapy in breast cancer. The prevalence and significance of ESR1 amplification in breast cancer remain controversial. We set out to assess ESR1 status and its relevance in breast cancer in Taiwan. We tested tissue samples from 311 invasive carcinomas in a tissue microarray for ESR1 status by fluorescent in situ hybridization (FISH) and chromogenic in situ hybridization (CISH). In order to examine its association with ERα and ESR1 status, HER2 status was determined by FISH. Of the carcinomas, 58.8 % (183/311) was ERα positive. None of the carcinomas showed amplification of ESR1 by either method, whereas 24.1 % (75/311) of the carcinomas harbored HER2 amplification. Of the carcinomas, 9.6 % (26/301) showed ESR1 gain (1.3 ≤ ratio ESR1/chromosome 6 < 2) by FISH and 10 % (24/299) by CISH. FISH and CISH results showed a good correlation (κ-coefficient = 0.786). ESR1 gain by FISH and CISH was significantly associated with high-grade (P = 0.0294 and 0.0417, respectively) but not with ERα expression, HER2 status, or overall survival. ERα positivity was significantly associated with better overall survival (P = 0.039). HER2 amplification was significantly related with poor overall survival (P = 0.002). Our data confirm that in breast cancer, HER2 amplification is a frequent genetic aberration and a negative prognostic factor, and show that ESR1 amplification is not a key genetic abnormality in the tumorigenesis of breast cancer in Taiwan.
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Affiliation(s)
- Jim-Ray Chen
- Department of Pathology, Keelung Chang Gung Memorial Hospital, 222 Maijin Road, Keelung, 204, Taiwan,
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23
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Jeselsohn R, Yelensky R, Buchwalter G, Frampton G, Meric-Bernstam F, Gonzalez-Angulo AM, Ferrer-Lozano J, Perez-Fidalgo JA, Cristofanilli M, Gómez H, Arteaga CL, Giltnane J, Balko JM, Cronin MT, Jarosz M, Sun J, Hawryluk M, Lipson D, Otto G, Ross JS, Dvir A, Soussan-Gutman L, Wolf I, Rubinek T, Gilmore L, Schnitt S, Come SE, Pusztai L, Stephens P, Brown M, Miller VA. Emergence of constitutively active estrogen receptor-α mutations in pretreated advanced estrogen receptor-positive breast cancer. Clin Cancer Res 2014; 20:1757-1767. [PMID: 24398047 DOI: 10.1158/1078-0432.ccr-13-2332] [Citation(s) in RCA: 510] [Impact Index Per Article: 46.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
PURPOSE We undertook this study to determine the prevalence of estrogen receptor (ER) α (ESR1) mutations throughout the natural history of hormone-dependent breast cancer and to delineate the functional roles of the most commonly detected alterations. EXPERIMENTAL DESIGN We studied a total of 249 tumor specimens from 208 patients. The specimens include 134 ER-positive (ER(+)/HER2(-)) and, as controls, 115 ER-negative (ER(-)) tumors. The ER(+) samples consist of 58 primary breast cancers and 76 metastatic samples. All tumors were sequenced to high unique coverage using next-generation sequencing targeting the coding sequence of the estrogen receptor and an additional 182 cancer-related genes. RESULTS Recurring somatic mutations in codons 537 and 538 within the ligand-binding domain of ER were detected in ER(+) metastatic disease. Overall, the frequency of these mutations was 12% [9/76; 95% confidence interval (CI), 6%-21%] in metastatic tumors and in a subgroup of patients who received an average of 7 lines of treatment the frequency was 20% (5/25; 95% CI, 7%-41%). These mutations were not detected in primary or treatment-naïve ER(+) cancer or in any stage of ER(-) disease. Functional studies in cell line models demonstrate that these mutations render estrogen receptor constitutive activity and confer partial resistance to currently available endocrine treatments. CONCLUSIONS In this study, we show evidence for the temporal selection of functional ESR1 mutations as potential drivers of endocrine resistance during the progression of ER(+) breast cancer.
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Affiliation(s)
- Rinath Jeselsohn
- Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, 450 Brookline Ave. Boston, MA 02215.,Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215
| | - Roman Yelensky
- Foundation Medicine, One Kendall Sq. Cambridge, MA 02139
| | - Gilles Buchwalter
- Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, 450 Brookline Ave. Boston, MA 02215.,Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215
| | | | - Funda Meric-Bernstam
- Departments of Investigational Cancer Therapeutics, Surgical Oncology, The University of MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030
| | - Ana Maria Gonzalez-Angulo
- Departments of Systems Biology, and Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030
| | - Jaime Ferrer-Lozano
- Fundacion de Investigacion INCLIVA - Institute for Health Reseearch, Valencia, Spain
| | - Jose A Perez-Fidalgo
- Departments of Hematology-Oncology, Hospital Clinico Universitario de Valencia, Valencia, Spain
| | - Massimo Cristofanilli
- Jefferson Breast Care Center, Kimmel Cancer Center, Thomas Jefferson University, 925 Chestnut St. Philadelphia, PA 19107
| | - Henry Gómez
- Instituto Nacional de Enfermedades Neoplásicas (INEN), Lima, Perú
| | - Carlos L Arteaga
- Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2220 Pierce Ave, Nashville, TN 37232
| | - Jennifer Giltnane
- Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2220 Pierce Ave, Nashville, TN 37232
| | - Justin M Balko
- Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2220 Pierce Ave, Nashville, TN 37232
| | | | - Mirna Jarosz
- Foundation Medicine, One Kendall Sq. Cambridge, MA 02139
| | - James Sun
- Foundation Medicine, One Kendall Sq. Cambridge, MA 02139
| | | | - Doron Lipson
- Foundation Medicine, One Kendall Sq. Cambridge, MA 02139
| | - Geoff Otto
- Foundation Medicine, One Kendall Sq. Cambridge, MA 02139
| | - Jeffrey S Ross
- Foundation Medicine, One Kendall Sq. Cambridge, MA 02139
| | - Addie Dvir
- Teva Pharmaceuticals, 5 Basel St. Petach Tikva, Israel 49131
| | | | - Ido Wolf
- Oncology Division, Tel Aviv Sourasky Medical Center , 6 Weizmann St. Tel Aviv 64239, Israel
| | - Tamar Rubinek
- Oncology Division, Tel Aviv Sourasky Medical Center , 6 Weizmann St. Tel Aviv 64239, Israel
| | - Lauren Gilmore
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave. Boston MA 02215
| | - Stuart Schnitt
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave. Boston MA 02215
| | - Steven E Come
- Breast Medical Oncology Program, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave. Boston MA 02215
| | - Lajos Pusztai
- Section of Breast Medical Oncology, Yale School of Medicine, New Haven, South Frontage Rd and Park St. CN, 06510
| | | | - Myles Brown
- Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, 450 Brookline Ave. Boston, MA 02215.,Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215
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Xiang Y, Zhang J, Huang K. Mining the tissue-tissue gene co-expression network for tumor microenvironment study and biomarker prediction. BMC Genomics 2013; 14 Suppl 5:S4. [PMID: 24564578 PMCID: PMC3852209 DOI: 10.1186/1471-2164-14-s5-s4] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Recent discovery in tumor development indicates that the tumor microenvironment (mostly stroma cells) plays an important role in cancer development. To understand how the tumor microenvironment (TME) interacts with the tumor, we explore the correlation of the gene expressions between tumor and stroma. The tumor and stroma gene expression data are modeled as a weighted bipartite network (tumor-stroma coexpression network) where the weight of an edge indicates the correlation between the expression profiles of the corresponding tumor gene and stroma gene. In order to efficiently mine this weighted bipartite network, we developed the Bipartite subnetwork Component Mining algorithm (BCM), and we show that the BCM algorithm can efficiently mine weighted bipartite networks for dense Bipartite sub-Networks (BiNets) with density guarantees. RESULTS We applied BCM to the tumor-stroma coexpression network and find 372 BiNets that demonstrate statistical significance in survival tests. A good number of these BiNets demonstrate strong prognosis powers on at least one breast cancer patient cohort, which suggests that these BiNets are potential biomarkers for breast cancer prognosis. Further study on these 372 BiNets by the network merging approach reveals that they form 10 macro bipartite networks which show orchestrated key biological processes in both tumor and stroma. In addition, by further examining the BiNets that are significant in ER-negative breast cancer patient prognosis, we discovered a ubiquitin C (UBC) gene network that demonstrates strong prognosis power in nearly all types of breast cancer subtypes we used in this study. CONCLUSIONS The results support our hypothesis that the UBC gene network plays an important role in breast cancer prognosis and therapy and it is a potential prognostic biomarker for multiple breast cancer subtypes.
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25
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Markiewicz A, Wełnicka-Jaśkiewicz M, Skokowski J, Jaśkiewicz J, Szade J, Jassem J, Żaczek AJ. Prognostic significance of ESR1 amplification and ESR1 PvuII, CYP2C19*2, UGT2B15*2 polymorphisms in breast cancer patients. PLoS One 2013; 8:e72219. [PMID: 23951298 PMCID: PMC3738574 DOI: 10.1371/journal.pone.0072219] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2013] [Accepted: 07/07/2013] [Indexed: 12/02/2022] Open
Abstract
Introduction Amplification of the ESR1 gene, coding for estrogen receptor alpha, was shown to predict responsiveness to tamoxifen, however its prognostic impact in breast cancer patients has not been thoroughly investigated. Other factors that could contribute to responsiveness to tamoxifen treatment are polymorphisms in ESR1 gene and genes involved in tamoxifen metabolism. The aim of this study was to assess the prognostic role of ESR1 gene dosage in a consecutive group of breast cancer patients and to correlate this feature with clinico-pathological factors. Additionally, ESR1 PvuII, CYP2C19*2 and UGT2B15*2 polymorphisms were analyzed in the tamoxifen-treated subgroup of patients. Materials and Methods Primary tumor samples from 281 stage I-III consecutive breast cancer patients were analyzed for ESR1 gene dosage using real-time PCR with locked nucleic acids hydrolysis probes. In the tamoxifen-treated subgroup of patients, ESR1 PvuII, CYP2C19*2 and UGT2B15*2 polymorphism in leukocytes genomic DNA were analyzed. Results were correlated with clinico-pathological factors and with disease-free survival (DFS) and overall survival (OS). Results ESR1 amplification (with a cut-off level of 2.0) was found in 12% of the entire group of breast cancer patients, and in 18% of the ER-negative subgroup. This feature was associated with decreased DFS both in the entire group (P=0.007) and in the ER-negative subgroup (P=0.03), but not in the tamoxifen-treated patients. Patients with ESR1 PvuII wt/wt genotype and at least one UGT2B15 wt allele had a worse DFS (P=0.03) and showed a trend towards decreased Os (P=0.08) in comparison to patients with ESR1 PvuII wt/vt or vt/vt genotype and UGT2B15 *2/*2 genotype. Conclusions ESR1 amplification can occur in ER-negative tumors and may carry poor prognosis. In the tamoxifen-treated subgroup, poor prognosis was related to the combined presence of ESR1 PvuII wt/wt and UGT2B15wt/wt or wt/*2 genotype.
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Affiliation(s)
- Aleksandra Markiewicz
- Department of Medical Biotechnology, Intercollegiate Faculty of Biotechnology, University of Gdańsk and Medical University of Gdańsk, Gdańsk, Poland
- PostgraduateSchool of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland
| | | | - Jarosław Skokowski
- Bank of Frozen Tissues and Genetic Specimens, Department of Medical Laboratory Diagnostics, Medical University of Gdańsk, Gdańsk, Poland
- Department of Surgical Oncology, Medical University of Gdańsk, Gdańsk, Poland
| | - Janusz Jaśkiewicz
- Department of Surgical Oncology, Medical University of Gdańsk, Gdańsk, Poland
| | - Jolanta Szade
- Department of Pathology, Medical University of Gdańsk, Gdańsk, Poland
| | - Jacek Jassem
- Department of Oncology and Radiotherapy, Medical University of Gdańsk, Gdańsk, Poland
| | - Anna J. Żaczek
- Department of Medical Biotechnology, Intercollegiate Faculty of Biotechnology, University of Gdańsk and Medical University of Gdańsk, Gdańsk, Poland
- * E-mail:
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Pentheroudakis G, Kotoula V, Eleftheraki AG, Tsolaki E, Wirtz RM, Kalogeras KT, Batistatou A, Bobos M, Dimopoulos MA, Timotheadou E, Gogas H, Christodoulou C, Papadopoulou K, Efstratiou I, Scopa CD, Papaspyrou I, Vlachodimitropoulos D, Linardou H, Samantas E, Pectasides D, Pavlidis N, Fountzilas G. Prognostic significance of ESR1 gene amplification, mRNA/protein expression and functional profiles in high-risk early breast cancer: a translational study of the Hellenic Cooperative Oncology Group (HeCOG). PLoS One 2013; 8:e70634. [PMID: 23923010 PMCID: PMC3726626 DOI: 10.1371/journal.pone.0070634] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2013] [Accepted: 06/25/2013] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Discrepant data have been published on the incidence and prognostic significance of ESR1 gene amplification in early breast cancer. PATIENTS AND METHODS Formalin-fixed paraffin-embedded tumor blocks were collected from women with early breast cancer participating in two HeCOG adjuvant trials. Messenger RNA was studied by quantitative PCR, ER protein expression was centrally assessed using immunohistochemistry (IHC) and ESR1 gene copy number by dual fluorescent in situ hybridization probes. RESULTS In a total of 1010 women with resected node-positive early breast adenocarcinoma, the tumoral ESR1/CEP6 gene ratio was suggestive of deletion in 159 (15.7%), gene gain in 551 (54.6%) and amplification in 42 cases (4.2%), with only 30 tumors (3%) harboring five or more ESR1 copies. Gene copy number ratio showed a significant, though weak correlation to mRNA and protein expression (Spearman's Rho <0.23, p = 0.01). ESR1 clusters were observed in 9.5% (57 gain, 38 amplification) of cases. In contrast to mRNA and protein expression, which were favorable prognosticators, gene copy number changes did not obtain prognostic significance. When ESR1/CEP6 gene ratio was combined with function (as defined by ER protein and mRNA expression) in a molecular classifier, the Gene Functional profile, it was functional status that impacted on prognosis. In univariate analysis, patients with functional tumors (positive ER protein expression and gene ratio normal or gain/amplification) fared better than those with non-functional tumors with ESR1 gain (HR for relapse or death 0.49-0.64, p = 0.003). Significant interactions were observed between gene gain/amplification and paclitaxel therapy (trend for DFS benefit from paclitaxel only in patients with ESR1 gain/amplification, p = 0.066) and Gene Functional profile with HER2 amplification (Gene Functional profile prognostic only in HER2-normal cases, p = 0.029). CONCLUSIONS ESR1 gene deletion and amplification do not constitute per se prognostic markers, instead they can be classified to distinct prognostic groups according to their protein-mediated functional status.
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Patani N, Martin LA, Dowsett M. Biomarkers for the clinical management of breast cancer: international perspective. Int J Cancer 2013; 133:1-13. [PMID: 23280579 DOI: 10.1002/ijc.27997] [Citation(s) in RCA: 131] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2012] [Accepted: 12/07/2012] [Indexed: 12/14/2022]
Abstract
The higher incidence of breast cancer in developed countries has been tempered by reductions in mortality, largely attributable to mammographic screening programmes and advances in adjuvant therapy. Optimal systemic management requires consideration of clinical, pathological and biological parameters. Oestrogen receptor alpha (ERα), progesterone receptor (PgR) and human epidermal growth factor receptor 2 (HER2) are established biomarkers evaluated at diagnosis, which identify cardinal subtypes of breast cancer. Their prognostic and predictive utility effectively guides systemic treatment with endocrine, anti-HER2 and chemotherapy. Hence, accurate and reliable determination remains of paramount importance. However, the goals of personalized medicine and targeted therapies demand further information regarding residual risk and potential benefit of additional treatments in specific circumstances. The need for biomarkers which are fit for purpose, and the demands placed upon them, is therefore expected to increase. Technological advances, in particular high-throughput global gene expression profiling, have generated multi-gene signatures providing further prognostic and predictive information. The rational integration of routinely evaluated clinico-pathological parameters with key indicators of biological activity, such as proliferation markers, also provides a ready opportunity to improve the information available to guide systemic therapy decisions. The additional value of such information and its proper place in patient management is currently under evaluation in prospective clinical trials. Expanding the utility of biomarkers to lower resource settings requires an emphasis on cost effectiveness, quality assurance and possible international variations in tumor biology; the potential for improved clinical outcomes should be justified against logistical and economic considerations.
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Affiliation(s)
- Neill Patani
- The Breakthrough Breast Cancer Research Center, The Institute of Cancer Research, London, United Kingdom
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Droog M, Beelen K, Linn S, Zwart W. Tamoxifen resistance: from bench to bedside. Eur J Pharmacol 2013; 717:47-57. [PMID: 23545365 DOI: 10.1016/j.ejphar.2012.11.071] [Citation(s) in RCA: 82] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2012] [Revised: 11/20/2012] [Accepted: 11/23/2012] [Indexed: 01/09/2023]
Abstract
Although tamoxifen is a classical example of a targeted drug, a substantial proportion of estrogen receptor alpha positive breast cancer patients does not benefit from the drug. Over the last few decades, many potential biomarkers have been discovered in cell biological studies that may aid in the prediction of tamoxifen sensitivity and guide in treatment selection. Nonetheless, the transition of such a biomarker from the scientific community towards a diagnostic test that can be used in daily clinical practice has been far from ideal, and such markers seldom face clinical introduction. From a large number of potential predictive biomarkers as described in cell biological literature, the clinical (translational) scientist has to make a decision which of these biomarkers should be tested in clinical material to determine their clinical validity. This problem is not trivial, since patient samples with clinical follow-up are a valuable asset that should therefore be cherished. In this review, we will describe a number of 'cell biological biomarkers' for tamoxifen resistance and their possible clinical implications. This may guide the clinical scientist in choosing what potential biomarkers to test on tumour samples, which may catalyse the translation of scientific discoveries into daily clinical practice of breast cancer medicine.
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Affiliation(s)
- Marjolein Droog
- Department of Molecular Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
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29
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Lin CH, Liu JM, Lu YS, Lan C, Lee WC, Kuo KT, Wang CC, Chang DY, Huang CS, Cheng AL. Clinical significance of ESR1 gene copy number changes in breast cancer as measured by fluorescence in situ hybridisation. J Clin Pathol 2012; 66:140-5. [PMID: 23268322 DOI: 10.1136/jclinpath-2012-200929] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
AIMS The ESR1 gene encodes for oestrogen receptor (ER) α, which plays a crucial role in mammary carcinogenesis and clinical outcome in patients with breast cancer. However, the clinical significance of the ESR1 gene copy number change for breast cancer has not been clarified. METHODS ESR1 gene copy number was determined by fluorescence in situ hybridisation (FISH) on tissue sections. A minimum of 20 tumour cells were counted per section, and a FISH ratio of ESR1 gene to CEP6 ≥ 2.0 was considered ESR1 amplification. A ratio >1.2 but <2.0 was considered ESR1 gain. The ESR1 copy number was further measured by quantitative real-time PCR (Q-PCR) with ASXL2 as a reference. RESULTS FISH revealed ESR1 amplification in six cases (4.0%) and ESR1 gain in 13 cases (8.7%) from a total of 150 cases. ESR1 gain and amplification were more common in older patients (p<0.001), and correlated well with ER protein expression (p=0.03) measured by immunohistochemistry, and ESR1 copy number (p<0.001) measured by Q-PCR. Furthermore, the multivariate analysis revealed that ESR1 amplification was associated with a shorter disease-free survival (HR=5.56, p=0.03) and a shorter overall survival (HR=5.11, p=0.04). CONCLUSIONS In general, the frequency of ESR1 amplification in breast cancer is low when measured by FISH in large sections. ESR1 gain and amplification in breast cancer may be associated with older age and poorer outcomes.
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Affiliation(s)
- Ching-Hung Lin
- Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
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30
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Garay JP, Park BH. Androgen receptor as a targeted therapy for breast cancer. Am J Cancer Res 2012; 2:434-45. [PMID: 22860233 PMCID: PMC3410582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2012] [Accepted: 05/15/2012] [Indexed: 06/01/2023] Open
Abstract
Breast cancer occurs at a high frequency in women and, given this fact, a primary focus of breast cancer research has been the study of estrogen receptor α (ER) signaling. However, androgens are known to play a role in normal breast physiology and therefore androgen receptor (AR) signaling is becoming increasingly recognized as an important contributor towards breast carcinogenesis. Moreover, the high frequency of AR expression in breast cancer makes it an attractive therapeutic target, but the ability to exploit AR for therapy has been difficult. Here we review the historical use of androgen/anti-androgen therapies in breast cancer, the challenges of accurately modeling nuclear hormone receptor signaling in vitro, and the presence and prognostic significance of AR in breast cancer.
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Affiliation(s)
- Joseph P Garay
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of MedicineBaltimore, MD, USA
| | - Ben H Park
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of MedicineBaltimore, MD, USA
- The Whiting School of Engineering, Department of Chemical and Biomolecular Engineering, The Johns Hopkins UniversityBaltimore, MD, USA
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31
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Laenkholm AV, Knoop A, Ejlertsen B, Rudbeck T, Jensen MB, Müller S, Lykkesfeldt AE, Rasmussen BB, Nielsen KV. ESR1 gene status correlates with estrogen receptor protein levels measured by ligand binding assay and immunohistochemistry. Mol Oncol 2012; 6:428-36. [PMID: 22626971 DOI: 10.1016/j.molonc.2012.04.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2012] [Accepted: 04/30/2012] [Indexed: 01/13/2023] Open
Abstract
The Estrogen Receptor (ER) is an established predictive marker for the selection of adjuvant endocrine treatment in early breast cancer. During the 1990s Immunohistochemistry (IHC) replaced cytosol based assays for determination of ER status. This study examined the association between ER protein level determined by two different methods and ESR1 gene copy number. From 289 primary high-risk breast cancer patients, randomized in the Danish Breast Cancer Cooperative Group (DBCG) 77C trial, results from cytosolic ER levels were available from ligand binding assays. Archival tumor tissue was retrieved from 257 patients. ESR1/CEN-6 ratio was analyzed successfully by Fluorescence In Situ Hybridization (FISH) in 220 (86%) patients. ESR1 amplification (ESR1/CEN-6 ≥ 2.00) was observed in 23% of the patients and ESR1 deletion (ESR1/CEN-6 < 0.80) was observed in 32%. Further, we identified ESR1 gain (ratio ESR1/CEN-6 from 1.30 to 1.99) in 19% of the patients. A positive correlation of ESR1 FISH with both ER-cytosol and ER IHC was found (p < 0.0001). Amplification and gain of the ESR1 gene are associated with higher ER protein content measured by ligand binding assay and a more intense nuclear staining by IHC compared to tumors with normal ESR1 gene status. Major variations in ER measured by ligand binding assay and IHC are observed within all ESR1 copy number subgroups and other mechanisms than gene copy number seem to contribute to the ER protein content in the tumors.
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Ejlertsen B, Aldridge J, Nielsen KV, Regan MM, Henriksen KL, Lykkesfeldt AE, Müller S, Gelber RD, Price KN, Rasmussen BB, Viale G, Mouridsen H. Prognostic and predictive role of ESR1 status for postmenopausal patients with endocrine-responsive early breast cancer in the Danish cohort of the BIG 1-98 trial. Ann Oncol 2012; 23:1138-1144. [PMID: 21986093 PMCID: PMC3335246 DOI: 10.1093/annonc/mdr438] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2011] [Revised: 08/10/2011] [Accepted: 08/19/2011] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND Estrogen Receptor 1 (ESR1) aberrations may be associated with expression of estrogen receptor (ER) or progesterone receptor (PgR), human epidermal growth factor receptor-2 (HER2) or Ki-67 labeling index and prognosis. PATIENTS AND METHODS ESR1 was assessed in 1129 (81%) of 1396 postmenopausal Danish women with early breast cancer randomly assigned to receive 5 years of letrozole, tamoxifen or a sequence of these agents in the Breast International Group 1-98 trial and who had ER ≥ 1% after central review. RESULTS By FISH, 13.6% of patients had an ESR1-to-Centromere-6 (CEN-6) ratio ≥ 2 (amplified), and 4.2% had ESR1-to-CEN-6 ratio <0.8 (deleted). Deletion of ESR1 was associated with significantly lower levels of ER (P < 0.0001) and PgR (P = 0.02) and more frequent HER2 amplification. ESR1 deletion or amplification was associated with higher-Ki-67 than ESR1-normal tumors. Overall, there was no evidence of heterogeneity of disease-free survival (DFS) or in treatment effect according to ESR1 status. However, significant differences in DFS were observed for subsets based on a combination of ESR1 and HER2 status (P = 0.02). CONCLUSIONS ESR1 aberrations were associated with HER2 status, Ki-67 labeling index and ER and PgR levels. When combined with HER2, ESR1 may be prognostic but should not be used for endocrine treatment selection in postmenopausal women with endocrine-responsive early breast cancer.
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Affiliation(s)
- B Ejlertsen
- Danish Breast Cancer Cooperative Group Statistical Center; Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
| | - J Aldridge
- International Breast Cancer Study Group Statistical Center, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, USA
| | | | - M M Regan
- International Breast Cancer Study Group Statistical Center, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, USA; Department of Biostatistics, Harvard School of Public Health; Department of Medicine, Harvard Medical School, Boston, USA
| | - K L Henriksen
- Department of Breast Cancer Research, Institute of Cancer Biology, Danish Cancer Society, Copenhagen, Denmark
| | - A E Lykkesfeldt
- Department of Breast Cancer Research, Institute of Cancer Biology, Danish Cancer Society, Copenhagen, Denmark
| | | | - R D Gelber
- International Breast Cancer Study Group Statistical Center, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, USA; Department of Biostatistics, Harvard School of Public Health; Department of Medicine, Harvard Medical School, Boston, USA; International Breast Cancer Study Group Statistical Center, Frontier Science and Technology Research Foundation, Boston, USA
| | - K N Price
- International Breast Cancer Study Group Statistical Center, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, USA; International Breast Cancer Study Group Statistical Center, Frontier Science and Technology Research Foundation, Boston, USA
| | - B B Rasmussen
- Department of Pathology, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark
| | - G Viale
- Division of Pathology and Laboratory Medicine, International Breast Cancer Study Group Pathology Review Office, European Institute of Oncology, University of Milan, Milan, Italy
| | - H Mouridsen
- Danish Breast Cancer Cooperative Group Statistical Center; Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
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Albertson DG. ESR1 amplification in breast cancer: controversy resolved? J Pathol 2012; 227:1-3. [PMID: 22322671 DOI: 10.1002/path.3999] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2012] [Revised: 01/26/2012] [Accepted: 01/27/2012] [Indexed: 12/19/2022]
Abstract
The determination of oestrogen receptor α (ERα) expression in breast cancers has been for many years the standard of care for guiding patient management. In 2007, Holst and colleagues published the previously unappreciated observation that the ERα gene, ESR1, was amplified in 21% of breast cancers, and that ESR1 gene amplification identified those individuals with high ERα expression in their tumours and who were likely to respond to hormonal manipulation. This has been a controversial area. Others have tried to reproduce these findings but the results have been mixed with respect to amplification frequency, and even contradictory with respect to prognostic and predictive value. The controversy may have now been resolved. Ooi et al, in this issue of the journal, show that the large clustered FISH signals that have been interpreted as ESR1 amplification are sensitive to RNase treatment, indicating that FISH is detecting accumulation of ESR1 transcripts in the nucleus of breast cancer cells expressing high levels of ERα, rather than gene amplification events. This story has important lessons for translational cancer research, and in particular FISH studies of gene copy number.
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Ooi A, Inokuchi M, Harada S, Inazawa J, Tajiri R, Kitamura SS, Ikeda H, Kawashima H, Dobashi Y. Gene amplification of ESR1 in breast cancers--fact or fiction? A fluorescence in situ hybridization and multiplex ligation-dependent probe amplification study. J Pathol 2012; 227:8-16. [PMID: 22170254 DOI: 10.1002/path.3974] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2011] [Revised: 11/29/2011] [Accepted: 12/02/2011] [Indexed: 01/03/2023]
Abstract
Oestrogen receptor-alpha (ERα), encoded by the ESR1 gene located on 6q25, is a nuclear transcription factor. Since it was reported in 2007 that more than 20% of breast cancers show ESR1 gene amplification, there has been considerable controversy about its frequency and clinical significance. We set out to assess the frequency and levels of ESR1 amplification in breast cancers. In a total of 106 breast needle biopsy specimens examined by immunohistochemistry, 78 tumours contained more than 10% ERα-positive cancer cells. In fluorescence in situ hybridization (FISH) analysis with an ESR1-specific probe, variously extended ESR1 signals were found in ERα-expressing cells. Some of these were indistinguishable from large clustered signals generally accepted to mean high-level gene amplification in homogeneously staining regions (HSRs), and could be considered to represent gene amplification. However, with RNase treatment, the 'HSR-like' signals changed to small compact signals, and are thus thought to represent concentrated RNA. FISH using two differently labelled probes corresponding to the non-overlapping 5'- and 3'-end portions of the ESR1 gene on touch smears showed a preserved spatial relationship of the 3' to 5' sequence of ESR1, therefore strongly suggesting that the RNA consisted of primary transcripts. Using touch smears obtained from 51 fresh tumours, precise enumeration of ESR1 signals with a correction by the number of centromere 6 on FISH after RNase A treatment revealed that three tumours (5.9%) had tumour cells with one to three additional copies of ESR1 as predominant subpopulations. This infrequent and low level of gene amplification of ESR1 was also detected as a 'gain' of the gene by analysis with multiplex ligation-dependent probe amplification (MLPA). The consistent results from immunohistochemistry, FISH, and MLPA in the present study settle the long-standing debate concerning gene amplification of ESR1 in breast carcinoma.
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Affiliation(s)
- Akishi Ooi
- Department of Molecular and Cellular Pathology, Graduate School of Medical Science, Kanazawa University, Ishikawa 920-8641, Japan.
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Yu KD, Shao ZM. ESR1 gene amplification: another mechanism regulating the cellular levels of ERα. Nat Rev Cancer 2011; 11:823; author reply 823. [PMID: 22020208 DOI: 10.1038/nrc3093-c1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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ESR1 amplification is rare in breast cancer and is associated with high grade and high proliferation: a multiplex ligation-dependent probe amplification study. Cell Oncol (Dordr) 2011; 34:489-94. [PMID: 21541733 PMCID: PMC3219866 DOI: 10.1007/s13402-011-0045-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/06/2010] [Indexed: 11/03/2022] Open
Abstract
Background Expression of estrogen receptor alpha (ERα) is predictive for endocrine therapy response and an important prognostic factor in breast cancer. Overexpression of ERα can be caused by estrogen receptor 1 (ESR1) gene amplification and was originally reported to be a frequent event associated with a significantly longer survival for ER-positive women treated with adjuvant tamoxifen monotherapy, which was however questioned by subsequent studies. Methods This study aimed to reanalyze the frequency of ESR1 amplification by multiplex ligation-dependent probe amplification (MLPA) and fluorescence in situ hybridisation (FISH), and to assess clinicopathologic correlations. MLPA was performed in a group of 135 breast cancer patients, and gains/amplifications were subjected to FISH. Results True ESR1 amplification by MLPA was rare (2%) and only 6% more patients showed a modest gain of ESR1. All MLPA-detected ESR1 amplifications and nearly all ESR1 gains were also FISH amplified and gained, but not all FISH amplifications/gains were MLPA amplified/gained, leading to an overall concordance of only 60% between both techniques. All 3 MLPA and FISH ESR1 amplified cases had high ERα expression, but there was no obvious correlation between ESR1 gain and ER status by IHC. ESR1 gains/amplifications were not associated with HER2 gain/amplification, but seemed to be associated with older age. Surprisingly, ESR1 gain/amplification was not associated with low grade as reported previously, but correlated with high grade and high proliferation. Furthermore, ESR1 gain/amplification by MLPA was not associated with nodal status or tumor size (pT status). Conclusions ESR1 amplification as detected by MLPA is rare in breast cancer, and seems to be associated with high ERα expression, high age, high grade and high proliferation. This study confirms previous studies that showed differences in the ESR1 amplification frequencies detected by different techniques. Electronic supplementary material The online version of this article (doi:10.1007/s13402-011-0045-5) contains supplementary material, which is available to authorized users.
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Miyoshi Y, Murase K, Saito M, Imamura M, Oh K. Mechanisms of estrogen receptor-α upregulation in breast cancers. Med Mol Morphol 2011; 43:193-6. [PMID: 21267694 DOI: 10.1007/s00795-010-0514-3] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2010] [Accepted: 04/20/2010] [Indexed: 12/28/2022]
Abstract
The most critical step for initiation and progression of estrogen receptor-α (ERα)-positive breast cancers is thought to be upregulation of ERα expression. There are several factors involved in this mechanism, i.e., increased promoter activity of the ERα gene (ESR1) at the transcriptional level, ESR1 gene amplification, and diminished degradation of ERα protein through ubiquitination and proteasomal pathways. Mediating these factors, ERα protein levels seem to be controlled, although the details of the mechanism remain to be clarified. In addition, for upregulation of estrogen signaling, functional changes in its action in cancer cells originating from normal epithelial cells, i.e., estrogen stimulation, which then leads to proliferation of ERα-positive cancer cells, has been recognized, but this action has not been observed in normal epithelial cells. These alterations are therefore likely to contribute to the pathogenesis of ERα-positive breast cancers.
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Affiliation(s)
- Yasuo Miyoshi
- Department of Surgery, Division of Breast and Endocrine Surgery, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan.
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Sanborn JZ, Benz SC, Craft B, Szeto C, Kober KM, Meyer L, Vaske CJ, Goldman M, Smith KE, Kuhn RM, Karolchik D, Kent WJ, Stuart JM, Haussler D, Zhu J. The UCSC Cancer Genomics Browser: update 2011. Nucleic Acids Res 2011; 39:D951-9. [PMID: 21059681 PMCID: PMC3013705 DOI: 10.1093/nar/gkq1113] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2010] [Accepted: 10/18/2010] [Indexed: 12/12/2022] Open
Abstract
The UCSC Cancer Genomics Browser (https://genome-cancer.ucsc.edu) comprises a suite of web-based tools to integrate, visualize and analyze cancer genomics and clinical data. The browser displays whole-genome views of genome-wide experimental measurements for multiple samples alongside their associated clinical information. Multiple data sets can be viewed simultaneously as coordinated 'heatmap tracks' to compare across studies or different data modalities. Users can order, filter, aggregate, classify and display data interactively based on any given feature set including clinical features, annotated biological pathways and user-contributed collections of genes. Integrated standard statistical tools provide dynamic quantitative analysis within all available data sets. The browser hosts a growing body of publicly available cancer genomics data from a variety of cancer types, including data generated from the Cancer Genome Atlas project. Multiple consortiums use the browser on confidential prepublication data enabled by private installations. Many new features have been added, including the hgMicroscope tumor image viewer, hgSignature for real-time genomic signature evaluation on any browser track, and 'PARADIGM' pathway tracks to display integrative pathway activities. The browser is integrated with the UCSC Genome Browser; thus inheriting and integrating the Genome Browser's rich set of human biology and genetics data that enhances the interpretability of the cancer genomics data.
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Affiliation(s)
- J. Zachary Sanborn
- Department of Biomolecular Engineering, Center for Biomolecular Science and Engineering and Howard Hughes Medical Institute, University of California at Santa Cruz, Santa Cruz, CA 95064, USA
| | - Stephen C. Benz
- Department of Biomolecular Engineering, Center for Biomolecular Science and Engineering and Howard Hughes Medical Institute, University of California at Santa Cruz, Santa Cruz, CA 95064, USA
| | - Brian Craft
- Department of Biomolecular Engineering, Center for Biomolecular Science and Engineering and Howard Hughes Medical Institute, University of California at Santa Cruz, Santa Cruz, CA 95064, USA
| | - Christopher Szeto
- Department of Biomolecular Engineering, Center for Biomolecular Science and Engineering and Howard Hughes Medical Institute, University of California at Santa Cruz, Santa Cruz, CA 95064, USA
| | - Kord M. Kober
- Department of Biomolecular Engineering, Center for Biomolecular Science and Engineering and Howard Hughes Medical Institute, University of California at Santa Cruz, Santa Cruz, CA 95064, USA
| | - Laurence Meyer
- Department of Biomolecular Engineering, Center for Biomolecular Science and Engineering and Howard Hughes Medical Institute, University of California at Santa Cruz, Santa Cruz, CA 95064, USA
| | - Charles J. Vaske
- Department of Biomolecular Engineering, Center for Biomolecular Science and Engineering and Howard Hughes Medical Institute, University of California at Santa Cruz, Santa Cruz, CA 95064, USA
| | - Mary Goldman
- Department of Biomolecular Engineering, Center for Biomolecular Science and Engineering and Howard Hughes Medical Institute, University of California at Santa Cruz, Santa Cruz, CA 95064, USA
| | - Kayla E. Smith
- Department of Biomolecular Engineering, Center for Biomolecular Science and Engineering and Howard Hughes Medical Institute, University of California at Santa Cruz, Santa Cruz, CA 95064, USA
| | - Robert M. Kuhn
- Department of Biomolecular Engineering, Center for Biomolecular Science and Engineering and Howard Hughes Medical Institute, University of California at Santa Cruz, Santa Cruz, CA 95064, USA
| | - Donna Karolchik
- Department of Biomolecular Engineering, Center for Biomolecular Science and Engineering and Howard Hughes Medical Institute, University of California at Santa Cruz, Santa Cruz, CA 95064, USA
| | - W. James Kent
- Department of Biomolecular Engineering, Center for Biomolecular Science and Engineering and Howard Hughes Medical Institute, University of California at Santa Cruz, Santa Cruz, CA 95064, USA
| | - Joshua M. Stuart
- Department of Biomolecular Engineering, Center for Biomolecular Science and Engineering and Howard Hughes Medical Institute, University of California at Santa Cruz, Santa Cruz, CA 95064, USA
| | - David Haussler
- Department of Biomolecular Engineering, Center for Biomolecular Science and Engineering and Howard Hughes Medical Institute, University of California at Santa Cruz, Santa Cruz, CA 95064, USA
| | - Jingchun Zhu
- Department of Biomolecular Engineering, Center for Biomolecular Science and Engineering and Howard Hughes Medical Institute, University of California at Santa Cruz, Santa Cruz, CA 95064, USA
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Olivo-Marston SE, Mechanic LE, Mollerup S, Bowman ED, Remaley AT, Forman MR, Skaug V, Zheng YL, Haugen A, Harris CC. Serum estrogen and tumor-positive estrogen receptor-alpha are strong prognostic classifiers of non-small-cell lung cancer survival in both men and women. Carcinogenesis 2010; 31:1778-86. [PMID: 20729390 DOI: 10.1093/carcin/bgq156] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The role of tumor estrogen receptors (ERs) and serum estrogen in lung cancer is inconclusive. We investigated the hypothesis that ERs and functional single-nucleotide polymorphisms in the estrogen biosynthesis pathway are associated with poorer lung cancer survival. Lung cancer patients (n = 305) from a National Cancer Institute-Maryland (NCI-MD) case-case cohort in the Baltimore metropolitan area were used as a test cohort. To validate, 227 cases from the NCI-MD case-control cohort and 293 cases from a Norwegian lung cancer cohort were studied. Information on demographics, tobacco and reproductive histories was collected in an interviewer-administered questionnaire. Serum estrogen, progesterone, tumor messenger RNA expression of hormone receptors and germ line DNA polymorphisms were analyzed for associations with lung cancer survival. Patients in the highest tertile of serum estrogen had worse survival in all three cohorts (P combined < 0.001). Furthermore, the variant allele of estrogen receptor alpha (ER-α) polymorphism (rs2228480) was significantly associated with increased tumor ER-α levels and worse survival in all three cohorts [hazard ratio (HR) = 2.59, 95% confidence interval (CI): 1.20- 4.01; HR = 1.76, 95% CI: 1.08-2.87 and HR = 2.85, 95% CI: 1.31-4.36). Other polymorphisms associated with lower serum estrogen correlated with improved survival. Results were independent of gender and hormone replacement therapy. We report a significant association of increased serum estrogen with poorer survival among lung cancer male and female patients. Understanding the genetic control of estrogen biosynthesis and response in lung cancer could lead to improved prognosis and therapy.
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Affiliation(s)
- Susan E Olivo-Marston
- Laboratory of Human Carcinogenesis, National Cancer Institute, Center for Cancer Research, National Institutes of Health, Bethesda, MD 20892, USA
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Biological reprogramming in acquired resistance to endocrine therapy of breast cancer. Oncogene 2010; 29:6071-83. [PMID: 20711236 DOI: 10.1038/onc.2010.333] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Endocrine therapies targeting the proliferative effect of 17β-estradiol through estrogen receptor α (ERα) are the most effective systemic treatment of ERα-positive breast cancer. However, most breast tumors initially responsive to these therapies develop resistance through molecular mechanisms that are not yet fully understood. The long-term estrogen-deprived (LTED) MCF7 cell model has been proposed to recapitulate acquired resistance to aromatase inhibitors in postmenopausal women. To elucidate this resistance, genomic, transcriptomic and molecular data were integrated into the time course of MCF7-LTED adaptation. Dynamic and widespread genomic changes were observed, including amplification of the ESR1 locus consequently linked to an increase in ERα. Dynamic transcriptomic profiles were also observed that correlated significantly with genomic changes and were predicted to be influenced by transcription factors known to be involved in acquired resistance or cell proliferation (for example, interferon regulatory transcription factor 1 and E2F1, respectively) but, notably, not by canonical ERα transcriptional function. Consistently, at the molecular level, activation of growth factor signaling pathways by EGFR/ERBB/AKT and a switch from phospho-Ser118 (pS118)- to pS167-ERα were observed during MCF7-LTED adaptation. Evaluation of relevant clinical settings identified significant associations between MCF7-LTED and breast tumor transcriptome profiles that characterize ERα-negative status, early response to letrozole and tamoxifen, and recurrence after tamoxifen treatment. In accordance with these profiles, MCF7-LTED cells showed increased sensitivity to inhibition of FGFR-mediated signaling with PD173074. This study provides mechanistic insight into acquired resistance to endocrine therapies of breast cancer and highlights a potential therapeutic strategy.
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Sugimura H, Mori H, Nagura K, Kiyose SI, Tao H, Isozaki M, Igarashi H, Shinmura K, Hasegawa A, Kitayama Y, Tanioka F. Fluorescence in situ hybridization analysis with a tissue microarray: 'FISH and chips' analysis of pathology archives. Pathol Int 2010; 60:543-550. [PMID: 20618731 DOI: 10.1111/j.1440-1827.2010.02561.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Practicing pathologists expect major somatic genetic changes in cancers, because the morphological deviations in the cancers they diagnose are so great that the somatic genetic changes to direct these phenotypes of tumors are supposed to be correspondingly tremendous. Several lines of evidence, especially lines generated by high-throughput genomic sequencing and genome-wide analyses of cancer DNAs are verifying their preoccupations. This article reviews a comprehensive morphological approach to pathology archives that consists of fluorescence in situ hybridization with bacterial artificial chromosome (BAC) probes and screening with tissue microarrays to detect structural changes in chromosomes (copy number alterations and rearrangements) in specimens of human solid tumors. The potential of this approach in the attempt to provide individually tailored medical practice, especially in terms of cancer therapy, is discussed.
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Affiliation(s)
- Haruhiko Sugimura
- Department of Pathology, Hamamamatsu University School of Medicine, 1-20-1, Handayama, Higashi-ward, Hamamatsu 431-3192, Japan.
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McCaughan F, Pole JCM, Bankier AT, Konfortov BA, Carroll B, Falzon M, Rabbitts TH, George PJ, Dear PH, Rabbitts PH. Progressive 3q amplification consistently targets SOX2 in preinvasive squamous lung cancer. Am J Respir Crit Care Med 2010; 182:83-91. [PMID: 20299530 PMCID: PMC2902760 DOI: 10.1164/rccm.201001-0005oc] [Citation(s) in RCA: 89] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2010] [Accepted: 03/17/2010] [Indexed: 11/16/2022] Open
Abstract
RATIONALE Amplification of distal 3q is the most common genomic aberration in squamous lung cancer (SQC). SQC develops in a multistage progression from normal bronchial epithelium through dysplasia to invasive disease. Identifying the key driver events in the early pathogenesis of SQC will facilitate the search for predictive molecular biomarkers and the identification of novel molecular targets for chemoprevention and therapeutic strategies. For technical reasons, previous attempts to analyze 3q amplification in preinvasive lesions have focused on small numbers of predetermined candidate loci rather than an unbiased survey of copy-number variation. OBJECTIVES To perform a detailed analysis of the 3q amplicon in bronchial dysplasia of different histological grades. METHODS We use molecular copy-number counting (MCC) to analyze the structure of chromosome 3 in 19 preinvasive bronchial biopsy specimens from 15 patients and sequential biopsy specimens from 3 individuals. MEASUREMENTS AND MAIN RESULTS We demonstrate that no low-grade lesions, but all high-grade lesions, have 3q amplification. None of seven low-grade lesions progressed clinically, whereas 8 of 10 patients with high-grade disease progressed to cancer. We identify a minimum commonly amplified region on chromosome 3 consisting of 17 genes, including 2 known oncogenes, SOX2 and PIK3CA. We confirm that both genes are amplified in all high-grade dysplastic lesions tested. We further demonstrate, in three individuals, that the clinical progression of high-grade preinvasive disease is associated with incremental amplification of SOX2, suggesting this promotes malignant progression. CONCLUSIONS These findings demonstrate progressive 3q amplification in the evolution of preinvasive SQC and implicate SOX2 as a key target of this dynamic process.
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Affiliation(s)
- Frank McCaughan
- Centre for Respiratory Research, Royal Free and University College Medical School, London, United Kingdom.
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Nielsen KV, Ejlertsen B, Müller S, Møller S, Rasmussen BB, Balslev E, Lænkholm AV, Christiansen P, Mouridsen HT. Amplification of ESR1 may predict resistance to adjuvant tamoxifen in postmenopausal patients with hormone receptor positive breast cancer. Breast Cancer Res Treat 2010; 127:345-55. [PMID: 20556506 DOI: 10.1007/s10549-010-0984-y] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2010] [Accepted: 06/04/2010] [Indexed: 12/27/2022]
Abstract
The estrogen receptor (ER) is the target of tamoxifen, but endocrine therapies do not benefit all patients with ER positive tumors. We therefore hypothesized that copy number changes in the ESR1 gene, encoding ER, confer resistance. Within a consecutive series of ER positive, postmenopausal patients allocated to 5 years tamoxifen, we identified 61 patients with recurrence less than 4 years and 48 patients without recurrence at least 7 years after initiation of adjuvant tamoxifen. Archival tissue containing primary tumor was collected from 97 patients (89%). Tumor samples were analyzed for ESR1 copy number changes using FISH with a probe covering the ESR1 gene at 6q25 and a reference probe covering the centromere of chromosome 6. The assay was validated in a material of 120 normal breast samples. FISH analysis for ESR1 was successful in 91 patients (94%). Amplification (ratio ESR1/CEN-6 ≥ 2.0) was observed in 11 of 50 (22%) patients with early recurrence, compared to two of 41 (5%) patients without recurrence. The difference is statistically significant (P = 0.033). In both groups, two patients with ESR1 deletion (ratio ESR1/CEN-6 < 0.8) were identified. ESR1 amplification was significantly associated with poor disease-free survival (P = 0.0054) and overall survival (P = 0.0004). This pilot study supports our hypothesis that ESR1 amplification is associated with a poorer outcome following adjuvant treatment with tamoxifen in ER positive early breast cancer. This study also revealed the existence of ESR1 deletions. The prognostic and predictive impact of ESR1 copy number changes needs further exploration in clinical trials.
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Shiu KK, Natrajan R, Geyer FC, Ashworth A, Reis-Filho JS. DNA amplifications in breast cancer: genotypic-phenotypic correlations. Future Oncol 2010; 6:967-84. [PMID: 20528234 DOI: 10.2217/fon.10.56] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
DNA copy number changes in cancer cells, in particular, amplifications, occur frequently, have prognostic impact and are associated with subtypes of breast cancer. Some amplicons contain well-characterized oncogenes, including 11q13 (CCND1) and 17q12 (HER2). HER2 amplification and overexpression defines the HER2+ subgroup of breast cancer patients and is both a prognostic marker for poor outcome and a predictive marker for response to anti-HER2 targeted therapies. Therefore, there is considerable interest in documenting the locations of other recurring amplifications in breast cancers as they may also provide a rich source of new biomarkers and novel therapeutic targets for these subgroups. This article focuses on the genomic profiling of breast cancer, with an emphasis on the characteristics of the amplifications found in subtypes of breast cancer, including luminal (ER+)/HER2(-)), HER2+ and basal-like (ER(-)/HER2(-)), and discusses their known or potential roles in cancer biology and their clinical implications.
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Affiliation(s)
- Kai-Keen Shiu
- The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, 237 Fulham Road, London SW36JB, UK
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45
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Pedraza V, Gomez-Capilla JA, Escaramis G, Gomez C, Torné P, Rivera JM, Gil A, Araque P, Olea N, Estivill X, Fárez-Vidal ME. Gene expression signatures in breast cancer distinguish phenotype characteristics, histologic subtypes, and tumor invasiveness. Cancer 2010; 116:486-96. [DOI: 10.1002/cncr.24805] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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46
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Burkhardt L, Grob TJ, Hermann I, Burandt E, Choschzick M, Jänicke F, Müller V, Bokemeyer C, Simon R, Sauter G, Wilczak W, Lebeau A. Gene amplification in ductal carcinoma in situ of the breast. Breast Cancer Res Treat 2009; 123:757-65. [PMID: 20033484 DOI: 10.1007/s10549-009-0675-8] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2009] [Accepted: 12/03/2009] [Indexed: 01/31/2023]
Abstract
Multiple different biologically and clinically relevant genes are often amplified in invasive breast cancer, including HER2, ESR1, CCND1, and MYC. So far, little is known about their role in tumor progression. To investigate their significance for tumor invasion, we compared pure ductal carcinoma in situ (DCIS) and DCIS associated with invasive cancer with regard to the amplification of these genes. Fluorescence in situ hybridization (FISH) was performed on a tissue microarray containing samples from 130 pure DCIS and 159 DCIS associated with invasive breast cancer. Of the latter patients, we analyzed the intraductal and invasive components separately. In addition, lymph node metastases of 23 patients with invasive carcinoma were included. Amplification rates of pure DCIS and DCIS associated with invasive cancer did not differ significantly (pure DCIS vs. DCIS associated with invasive cancer: HER2 22.7 vs. 24.2%, ESR1 19.0 vs. 24.1%, CCND1 10.0 vs. 14.8%, MYC 11.8 vs. 6.5%; P > 0.05). Furthermore, we observed a high concordance of the amplification status for all genes if in situ and invasive carcinoma of individual patients were compared. This applied also to the corresponding lymph node metastases. Our results indicate no significant differences between the gene amplification status of DCIS and invasive breast cancer concerning HER2, ESR1, CCND1, and MYC. Therefore, our data suggest an early role of all analyzed gene amplifications in breast cancer development but not in the initiation of invasive tumor growth.
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MESH Headings
- Adult
- Aged
- Aged, 80 and over
- Breast Neoplasms/genetics
- Breast Neoplasms/pathology
- Carcinoma, Ductal, Breast/genetics
- Carcinoma, Ductal, Breast/pathology
- Carcinoma, Intraductal, Noninfiltrating/genetics
- Carcinoma, Intraductal, Noninfiltrating/pathology
- Chi-Square Distribution
- Cyclin D1/genetics
- Estrogen Receptor alpha/genetics
- Female
- Gene Amplification
- Gene Expression Regulation, Neoplastic
- Genotype
- Humans
- In Situ Hybridization, Fluorescence
- Lymphatic Metastasis
- Middle Aged
- Neoplasm Invasiveness
- Phenotype
- Proto-Oncogene Proteins c-myc/genetics
- Receptor, ErbB-2/genetics
- Tissue Array Analysis
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Affiliation(s)
- L Burkhardt
- Department of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
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47
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Mackay A, Tamber N, Fenwick K, Iravani M, Grigoriadis A, Dexter T, Lord CJ, Reis-Filho JS, Ashworth A. A high-resolution integrated analysis of genetic and expression profiles of breast cancer cell lines. Breast Cancer Res Treat 2009; 118:481-98. [PMID: 19169812 DOI: 10.1007/s10549-008-0296-7] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2008] [Accepted: 12/23/2008] [Indexed: 10/21/2022]
Abstract
Tumour cell lines derived from breast cancer patients constitute one of the cornerstones of breast cancer research. To characterise breast cancer cell lines at the genetic level, we have developed a full tiling path bacterial artificial chromosome (BAC) array collection for comparative genomic hybridisation (aCGH). This aCGH BAC collection covers 98% of the entire human genome at a resolution of 40-60 kbp. We have used this platform alongside an in-house produced 17 K cDNA microarray set to characterise the genetic and transcriptomic profiles of 24 breast cancer cell lines, as well as cell types derived from non-diseased breast. We demonstrate that breast cancer cell lines have genomic and transcriptomic features that recapitulate those of primary breast cancers and can be reliably subclassified into basal-like and luminal subgroups. By overlaying aCGH and transcriptomic data, we have identified 753 genes whose expression correlate with copy number; this list comprised numerous oncogenes recurrently amplified and overexpressed in breast cancer (e.g., HER2, MYC, CCND1 and AURKA). Finally, we demonstrate that although breast cancer cell lines have genomic features usually found in grade III breast cancers (i.e., gains of 1q, 8q and 20q), basal-like and luminal cell lines are characterised by distinct genomic aberrations.
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Affiliation(s)
- Alan Mackay
- The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, Fulham Road, London, SW3 6JB, UK
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48
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Natrajan R, Weigelt B, Mackay A, Geyer FC, Grigoriadis A, Tan DSP, Jones C, Lord CJ, Vatcheva R, Rodriguez-Pinilla SM, Palacios J, Ashworth A, Reis-Filho JS. An integrative genomic and transcriptomic analysis reveals molecular pathways and networks regulated by copy number aberrations in basal-like, HER2 and luminal cancers. Breast Cancer Res Treat 2009; 121:575-89. [PMID: 19688261 DOI: 10.1007/s10549-009-0501-3] [Citation(s) in RCA: 122] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2009] [Accepted: 07/28/2009] [Indexed: 11/30/2022]
Abstract
Breast cancer is a heterogeneous disease caused by the accumulation of genetic changes in neoplastic cells. We hypothesised that molecular subtypes of breast cancer may be driven by specific constellations of genes whose expression is regulated by gene copy number aberrations. To address this question, we analysed a series of 48 microdissected grade III ductal carcinomas using high resolution microarray comparative genomic hybridisation and mRNA expression arrays. There were 5,931 genes whose expression significantly correlates with copy number identified; out of these, 1,897 genes were significantly differentially expressed between basal-like, HER2 and luminal tumours. Ingenuity Pathway Analysis (IPA) revealed that 'G1/S cell cycle regulation' and 'BRCA1 in DNA damage control' pathways were significantly enriched for genes whose expression correlates with copy number and are differentially expressed between the molecular subtypes of breast cancer. IPA of genes whose expression significantly correlates with copy number in each molecular subtype individually revealed that canonical pathways involved in oestrogen receptor (ER) signalling and DNA repair are enriched for these genes. We also identified 32, 157 and 265 genes significantly overexpressed when amplified in basal-like, HER2 and luminal cancers, respectively. These lists include known and novel potential therapeutic targets (e.g. HER2 and PPM1D in HER2 cancers). Our results provide strong circumstantial evidence that different patterns of genetic aberrations in distinct molecular subtypes of breast cancer contribute to their specific transcriptomic profiles and that biological phenomena characteristic of each subtype (e.g. proliferation, HER2 and ER signalling) may be driven by specific patterns of copy number aberrations.
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Affiliation(s)
- Rachael Natrajan
- The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
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49
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Tomita S, Zhang Z, Nakano M, Ibusuki M, Kawazoe T, Yamamoto Y, Iwase H. Estrogen receptor alpha gene ESR1 amplification may predict endocrine therapy responsiveness in breast cancer patients. Cancer Sci 2009; 100:1012-7. [PMID: 19320640 PMCID: PMC11159263 DOI: 10.1111/j.1349-7006.2009.01145.x] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
Estrogen receptor (ER) alpha plays a crucial role in normal breast development and has also been linked to mammary carcinogenesis and clinical outcome in breast cancer patients. However, the molecular mechanisms controlling the expression of ERalpha are as yet not fully understood. Gene amplification is one of the important factors regulating protein expression. Recent studies on the amplification of the ESR1 gene, which encodes ERalpha, have presented conflicting data. Using fluorescence in situ hybridization and real-time quantitative polymerase chain reaction analysis, we examined the ESR1 status in a series of breast cancer tissues and analyzed its clinical importance. ESR1 gene amplification and gain were found in 22.6 and 11.3% of samples, respectively, as determined by three-dimensional fluorescence in situ hybridization assay. Moreover, ESR1 amplification and amplification plus gain were significantly negatively correlated with tumor size, number of positive lymph nodes, negative ERalpha, and positive human epidermal growth factor receptor 2 status. It has also been shown that ESR1 amplification strongly correlates with higher expression levels of ER protein and that patients with ESR1 amplification in their tumors apparently experience longer disease-free survival than those without. Our data suggest that ESR1 amplification might prove to be helpful in selecting patients who may potentially benefit from endocrine therapy.
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Affiliation(s)
- Saori Tomita
- Department of Breast and Endocrine Surgery, Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
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50
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McCaughan F. Molecular copy-number counting: potential of single-molecule diagnostics. Expert Rev Mol Diagn 2009; 9:309-12. [PMID: 19435452 DOI: 10.1586/erm.09.14] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/31/2025]
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