Cirillo, Francesca (2013) Analysis of antagonist-liganded estrogen receptor alpha interactomes: new insights on antiestrogen activity in human breast cancer cells. [Tesi di dottorato]


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Item Type: Tesi di dottorato
Lingua: English
Title: Analysis of antagonist-liganded estrogen receptor alpha interactomes: new insights on antiestrogen activity in human breast cancer cells
Date: 30 March 2013
Number of Pages: 83
Institution: Università degli Studi di Napoli Federico II
Department: Medicina Molecolare e Biotecnologie Mediche
Scuola di dottorato: Medicina molecolare
Dottorato: Patologia e fisiopatologia molecolare
Ciclo di dottorato: 25
Coordinatore del Corso di dottorato:
Avvedimento, Vittorio
Date: 30 March 2013
Number of Pages: 83
Uncontrolled Keywords: estrogen receptor; antiestrogen; estradiol; tamoxifen; raloxifene; ICI 182780; breast cancer; histone H3 methyltransferase DOT1L; Deleted in breast cancer gene 1 KIAA1967; pyruvate dehydrogenase E1 component PDHA1
Settori scientifico-disciplinari del MIUR: Area 05 - Scienze biologiche > BIO/11 - Biologia molecolare
Area 06 - Scienze mediche > MED/04 - Patologia generale
Aree tematiche (7° programma Quadro): SALUTE e TUTELA DEL CONSUMATORE > Biotecnologie, strumenti e tecnologie generiche per la salute umana
BIOTECNOLOGIE, PRODOTTI ALIMENTARI E AGRICOLTURA > Scienze della vita, biotecnologia e biochimica per prodotti e processi non-alimentari sostenibili
Date Deposited: 10 Apr 2013 13:40
Last Modified: 22 Jul 2014 13:12
DOI: 10.6092/UNINA/FEDOA/9278


Estrogen receptor alpha (ERα) is a ligand activated transcription factor that controls key cellular pathways via protein−protein interactions involving multiple components of transcriptional coregulator and signal transduction complexes. Natural and synthetic ERα ligands are classified as agonists (17β-estradiol/E2), selective estrogen receptor modulators (SERMs: Tamoxifen/Tam and Raloxifene/ Ral), and pure antagonists (ICI 182,780-Fulvestrant/ ICI), according to the response they elicit in hormone responsive cells. Crystallographic analyses reveal ligand dependent ERα conformations, characterized by specific surface docking sites for functional protein−protein interactions, whose identification is needed to understand antiestrogen effects on estrogen target tissues, in particular breast cancer (BC). Tandem affinity purification (TAP) coupled to mass spectrometry was applied here to map nuclear ERα interactomes dependent upon different classes of ligands in hormone-responsive BC cells. Comparative analyses of agonist (E2)- vs antagonist (Tam, Ral or ICI)-bound ERα interacting proteins reveal significant differences among ER ligands that relate with their biological activity, identifying novel functional partners of antiestrogen−ERα complexes in human BC cell nuclei. In particular, the E2-dependent nuclear ERα interactome is different and more complex than those elicited by Tam, Ral, or ICI, which, in turn, are significantly divergent from each other, a result that provides clues to explain the pharmacological specificities of these compounds.


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