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Teresa Elo Departments of Cell Biology and Anatomy

Pharmacology Drug Development and Therapeutics

Turku Center for Disease Modeling Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, 20520 Turku, Finland

Functional Foods Forum University of Turku, Turku, Finland

Department of Laboratory Medicine MAS University Hospital, Lund University, Malmö, Sweden

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Lan Yu Departments of Cell Biology and Anatomy

Pharmacology Drug Development and Therapeutics

Turku Center for Disease Modeling Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, 20520 Turku, Finland

Functional Foods Forum University of Turku, Turku, Finland

Department of Laboratory Medicine MAS University Hospital, Lund University, Malmö, Sweden

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Eeva Valve Departments of Cell Biology and Anatomy

Pharmacology Drug Development and Therapeutics

Turku Center for Disease Modeling Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, 20520 Turku, Finland

Functional Foods Forum University of Turku, Turku, Finland

Department of Laboratory Medicine MAS University Hospital, Lund University, Malmö, Sweden

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Sari Mäkelä Departments of Cell Biology and Anatomy

Pharmacology Drug Development and Therapeutics

Turku Center for Disease Modeling Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, 20520 Turku, Finland

Functional Foods Forum University of Turku, Turku, Finland

Department of Laboratory Medicine MAS University Hospital, Lund University, Malmö, Sweden
Departments of Cell Biology and Anatomy

Pharmacology Drug Development and Therapeutics

Turku Center for Disease Modeling Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, 20520 Turku, Finland

Functional Foods Forum University of Turku, Turku, Finland

Department of Laboratory Medicine MAS University Hospital, Lund University, Malmö, Sweden

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Pirkko Härkönen Departments of Cell Biology and Anatomy

Pharmacology Drug Development and Therapeutics

Turku Center for Disease Modeling Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, 20520 Turku, Finland

Functional Foods Forum University of Turku, Turku, Finland

Department of Laboratory Medicine MAS University Hospital, Lund University, Malmö, Sweden
Departments of Cell Biology and Anatomy

Pharmacology Drug Development and Therapeutics

Turku Center for Disease Modeling Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, 20520 Turku, Finland

Functional Foods Forum University of Turku, Turku, Finland

Department of Laboratory Medicine MAS University Hospital, Lund University, Malmö, Sweden

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development of benign prostatic hyperplasia (BPH) and prostate cancer ( Härkönen & Mäkelä 2004 , Prins & Korach 2008 , Ellem & Risbridger 2009 , Hartman et al . 2012 ). In target tissues, estrogens act via estrogen receptor α (ERα) (ESR1) and ERβ (ESR2

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A L Chand Cancer Drug Discovery Laboratory, Department of Biochemistry, Invasion and Metastasis Laboratory, Prince Henry's Institute, 246 Clayton Road, Melbourne, Victoria 3168, Australia

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K A Herridge Cancer Drug Discovery Laboratory, Department of Biochemistry, Invasion and Metastasis Laboratory, Prince Henry's Institute, 246 Clayton Road, Melbourne, Victoria 3168, Australia
Cancer Drug Discovery Laboratory, Department of Biochemistry, Invasion and Metastasis Laboratory, Prince Henry's Institute, 246 Clayton Road, Melbourne, Victoria 3168, Australia

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E W Thompson Cancer Drug Discovery Laboratory, Department of Biochemistry, Invasion and Metastasis Laboratory, Prince Henry's Institute, 246 Clayton Road, Melbourne, Victoria 3168, Australia

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C D Clyne Cancer Drug Discovery Laboratory, Department of Biochemistry, Invasion and Metastasis Laboratory, Prince Henry's Institute, 246 Clayton Road, Melbourne, Victoria 3168, Australia
Cancer Drug Discovery Laboratory, Department of Biochemistry, Invasion and Metastasis Laboratory, Prince Henry's Institute, 246 Clayton Road, Melbourne, Victoria 3168, Australia

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also an ERα target gene ( Annicotte et al . 2005 ) in MCF-7 cells. To determine whether LRH-1-dependent cell migration occurs independently of oestrogen, we repeated these experiments using the ER-negative MDA-MB-231 cell line and obtained similar

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Amanda Schech Department of Pharmacology, Division of Biostatistics, Department of Medicine and Physiology, University of Maryland School of Medicine, University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, Maryland, USA

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Stephen Yu Department of Pharmacology, Division of Biostatistics, Department of Medicine and Physiology, University of Maryland School of Medicine, University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, Maryland, USA

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Olga Goloubeva Department of Pharmacology, Division of Biostatistics, Department of Medicine and Physiology, University of Maryland School of Medicine, University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, Maryland, USA

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John McLenithan Department of Pharmacology, Division of Biostatistics, Department of Medicine and Physiology, University of Maryland School of Medicine, University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, Maryland, USA

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Gauri Sabnis Department of Pharmacology, Division of Biostatistics, Department of Medicine and Physiology, University of Maryland School of Medicine, University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, Maryland, USA

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418 were obtained from Life Technologies. Human insulin and Matrigel were obtained from Sigma Chemical Company. Antibodies against phospho-ERα (S118 and S167) were purchased from Millipore (Billerica, MA, USA). Antibodies against p-Akt and Akt were

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Nathan R West Deeley Research Centre, Department of Biochemistry and Microbiology, Department of Biochemistry and Medical Genetics, Department of Pathology and Laboratory Medicine, BC Cancer Agency, 2410 Lee Avenue, 3rd Floor Research, Victoria, British Columbia, Canada V8R 6V5
Deeley Research Centre, Department of Biochemistry and Microbiology, Department of Biochemistry and Medical Genetics, Department of Pathology and Laboratory Medicine, BC Cancer Agency, 2410 Lee Avenue, 3rd Floor Research, Victoria, British Columbia, Canada V8R 6V5

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Leigh C Murphy Deeley Research Centre, Department of Biochemistry and Microbiology, Department of Biochemistry and Medical Genetics, Department of Pathology and Laboratory Medicine, BC Cancer Agency, 2410 Lee Avenue, 3rd Floor Research, Victoria, British Columbia, Canada V8R 6V5

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Peter H Watson Deeley Research Centre, Department of Biochemistry and Microbiology, Department of Biochemistry and Medical Genetics, Department of Pathology and Laboratory Medicine, BC Cancer Agency, 2410 Lee Avenue, 3rd Floor Research, Victoria, British Columbia, Canada V8R 6V5
Deeley Research Centre, Department of Biochemistry and Microbiology, Department of Biochemistry and Medical Genetics, Department of Pathology and Laboratory Medicine, BC Cancer Agency, 2410 Lee Avenue, 3rd Floor Research, Victoria, British Columbia, Canada V8R 6V5
Deeley Research Centre, Department of Biochemistry and Microbiology, Department of Biochemistry and Medical Genetics, Department of Pathology and Laboratory Medicine, BC Cancer Agency, 2410 Lee Avenue, 3rd Floor Research, Victoria, British Columbia, Canada V8R 6V5

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Introduction Oestrogen receptor alpha (ERα) is a central factor in breast cell biology and growth. As the primary transcription factor that mediates oestrogen signalling, ER is the linchpin of endocrine therapy and a feature that partly defines the

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Claudia Lanari Instituto de Biología y Medicina Experimental (IBYME‐CONICET), Oral and Pharyngeal Cancer Branch, Buenos Aires, Argentina

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Victoria Wargon Instituto de Biología y Medicina Experimental (IBYME‐CONICET), Oral and Pharyngeal Cancer Branch, Buenos Aires, Argentina

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Paola Rojas Instituto de Biología y Medicina Experimental (IBYME‐CONICET), Oral and Pharyngeal Cancer Branch, Buenos Aires, Argentina

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Alfredo A Molinolo Instituto de Biología y Medicina Experimental (IBYME‐CONICET), Oral and Pharyngeal Cancer Branch, Buenos Aires, Argentina

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express estrogen receptor alpha (ERα) and respond to antiestrogen therapies. These carcinomas may also express progesterone receptors (PRs), which are a reliable marker of functional ERs ( Kastner et al . 1990 , Petz & Nardulli 2000 ). In this paper, we

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Carol A Lange Departments of Medicine and Pharmacology, Masonic Cancer Center, University of Minnesota, 420 Delaware Street South East, MMC 806, Minneapolis Minnesota 55455, USA

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Douglas Yee Departments of Medicine and Pharmacology, Masonic Cancer Center, University of Minnesota, 420 Delaware Street South East, MMC 806, Minneapolis Minnesota 55455, USA

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transcriptional upregulation of cyclin D1 mRNA and protein expression ( Prall et al . 1998 ). In addition, membrane-associated ERα molecules induce rapid activation of c-Src and MAPKs and are capable of transactivation of epidermal growth factor (EGFR) in breast

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Yumi Endo Departments of Oncology, Experimental Pathology and Tumor Biology, Immunology and Surgery

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Tatsuya Toyama Departments of Oncology, Experimental Pathology and Tumor Biology, Immunology and Surgery

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Satoru Takahashi Departments of Oncology, Experimental Pathology and Tumor Biology, Immunology and Surgery

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Nobuyasu Yoshimoto Departments of Oncology, Experimental Pathology and Tumor Biology, Immunology and Surgery

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Mai Iwasa Departments of Oncology, Experimental Pathology and Tumor Biology, Immunology and Surgery

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Tomoko Asano Departments of Oncology, Experimental Pathology and Tumor Biology, Immunology and Surgery

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Yoshitaka Fujii Departments of Oncology, Experimental Pathology and Tumor Biology, Immunology and Surgery

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Hiroko Yamashita Departments of Oncology, Experimental Pathology and Tumor Biology, Immunology and Surgery

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Introduction There are large-scale molecular differences between estrogen receptor α (ERα)-positive and ER-negative breast cancers ( Sorlie et al . 2003 ). ER is essential for estrogen-dependent growth, and its level of expression is a crucial

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Vera Cappelletti Department of Experimental Oncology, Molecular Cancer Genetics, Departments of Medical Oncology, Surgery, Pathology, Scientific Direction, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milano, Italy

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Manuela Gariboldi Department of Experimental Oncology, Molecular Cancer Genetics, Departments of Medical Oncology, Surgery, Pathology, Scientific Direction, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milano, Italy
Department of Experimental Oncology, Molecular Cancer Genetics, Departments of Medical Oncology, Surgery, Pathology, Scientific Direction, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milano, Italy

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Loris De Cecco Department of Experimental Oncology, Molecular Cancer Genetics, Departments of Medical Oncology, Surgery, Pathology, Scientific Direction, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milano, Italy
Department of Experimental Oncology, Molecular Cancer Genetics, Departments of Medical Oncology, Surgery, Pathology, Scientific Direction, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milano, Italy

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Sara Toffanin Department of Experimental Oncology, Molecular Cancer Genetics, Departments of Medical Oncology, Surgery, Pathology, Scientific Direction, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milano, Italy

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James F Reid Department of Experimental Oncology, Molecular Cancer Genetics, Departments of Medical Oncology, Surgery, Pathology, Scientific Direction, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milano, Italy
Department of Experimental Oncology, Molecular Cancer Genetics, Departments of Medical Oncology, Surgery, Pathology, Scientific Direction, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milano, Italy

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Lara Lusa Department of Experimental Oncology, Molecular Cancer Genetics, Departments of Medical Oncology, Surgery, Pathology, Scientific Direction, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milano, Italy
Department of Experimental Oncology, Molecular Cancer Genetics, Departments of Medical Oncology, Surgery, Pathology, Scientific Direction, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milano, Italy

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Emilio Bajetta Department of Experimental Oncology, Molecular Cancer Genetics, Departments of Medical Oncology, Surgery, Pathology, Scientific Direction, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milano, Italy

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Luigi Celio Department of Experimental Oncology, Molecular Cancer Genetics, Departments of Medical Oncology, Surgery, Pathology, Scientific Direction, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milano, Italy

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Marco Greco Department of Experimental Oncology, Molecular Cancer Genetics, Departments of Medical Oncology, Surgery, Pathology, Scientific Direction, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milano, Italy

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Alessandra Fabbri Department of Experimental Oncology, Molecular Cancer Genetics, Departments of Medical Oncology, Surgery, Pathology, Scientific Direction, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milano, Italy

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Marco A Pierotti Department of Experimental Oncology, Molecular Cancer Genetics, Departments of Medical Oncology, Surgery, Pathology, Scientific Direction, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milano, Italy
Department of Experimental Oncology, Molecular Cancer Genetics, Departments of Medical Oncology, Surgery, Pathology, Scientific Direction, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milano, Italy

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Maria Grazia Daidone Department of Experimental Oncology, Molecular Cancer Genetics, Departments of Medical Oncology, Surgery, Pathology, Scientific Direction, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milano, Italy

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This study aimed to define a gene expression profile associated with response to anti-estrogen treatment in estrogen receptor α (ERα)-positive breast cancer from elderly patients and to identify possible candidate genes associated with resistance by detecting those modulated by treatment. Using cDNA microarrays containing 16 702 unique clones, 21 pre-treatment and 11 paired post-treatment samples collected in a neo-adjuvant toremifene trial on elderly patients with operable and locally advanced ERα-positive breast cancer were profiled. Gene expression profiles generated from pre-treatment samples were correlated with treatment-induced tumor shrinkage and compared with those obtained from post-treatment paired samples to define genes differentially modulated following anti-estrogen treatment. Correlation analysis on 21 pre-treatment samples highlighted 53 genes significantly related to treatment response (P<0.001). Genes involved in cell cycle and proliferation were more frequently upregulated in responders compared with non-responders. Class comparison analysis identified 101 genes significantly modulated independently of treatment response; 82 genes were modulated in non-responders, whereas only 8 genes were differently expressed after treatment in responders. Gene expression profiles appear to be more frequently modulated by anti-estrogen treatment in non-responding patients and may harbor interesting genes possibly involved in anti-estrogen resistance, including clusterin, MAPK6, and MMP2. This concept was corroborated by in vitro studies showing that silencing of CLU restored toremifene sensitivity in the ER anti-estrogen-resistant breast cancer cell line T47D. Integration between neo-adjuvant therapy and transcriptional profiling has therefore the potential to identify therapeutic targets to be challenged for overcoming treatment resistance.

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R I Nicholson Tenovus Centre for Cancer Research, Welsh School of Pharmacy, Cardiff University, Cardiff, UK

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C Staka Tenovus Centre for Cancer Research, Welsh School of Pharmacy, Cardiff University, Cardiff, UK

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F Boyns Tenovus Centre for Cancer Research, Welsh School of Pharmacy, Cardiff University, Cardiff, UK

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I R Hutcheson Tenovus Centre for Cancer Research, Welsh School of Pharmacy, Cardiff University, Cardiff, UK

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J M W Gee Tenovus Centre for Cancer Research, Welsh School of Pharmacy, Cardiff University, Cardiff, UK

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deprivation provides an effective therapeutic second line strategy in advanced postmenopausal estrogen receptor positive (ERα+) breast cancer ( Johnston & Dowsett 2003 ). Moreover, emerging trial data indicate that AIs may be superior to the antiestrogen

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R A Stein Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA

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D P McDonnell Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA

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Introduction Drugs that function by inhibiting ERα signaling have been and will continue to be an important part of pharmacotherapy in breast cancer. Foremost among these therapies are selective estrogen receptor modulators (SERMs

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