Descrizione del progetto DEENESFRITPL Studio del cross-talk ormonale nel tumore al seno La maggior parte dei tumori al seno è guidata dai recettori per gli estrogeni (ER) e i farmaci anti-estrogenici rappresentano il trattamento standard per questi tumori. Studi recenti sostengono l’attivazione del recettore del progesterone (PR) per trattare i casi in cui il cancro diventa resistente ai farmaci anti-estrogenici. La controversia sul ruolo dei progestinici in questa malattia impedisce l’applicazione clinica di terapie mirate al PR. Il progetto ER_disease, finanziato dal CER, si concentra sullo studio del cross-talk tra i recettori nucleari nel tumore al seno. L’obiettivo principale è quello di verificare l’ipotesi che altri recettori nucleari presenti in questi tessuti tumorali possano essere attivati per interferire con la funzione degli ER e prevenire la progressione del tumore al seno. Mostra l’obiettivo del progetto Nascondi l’obiettivo del progetto Obiettivo Estrogen Receptor (ER) is the driving transcription factor in ~75% of all breast cancers. ER antagonists are routinely used for treatment, but significant variability exists in clinical response. We are interested in explaining this heterogeneity and exploiting the mechanistic insight. We have recently identified important, but previously uncharacterised cross-talk between ER and the progesterone receptor (PR) and androgen receptor (AR) pathways, both of which are commonly expressed in ER+ tumours. Recently, ER has been shown to be mutated in ~18-55% of metastatic breast cancers. In addition, two key ER-chromatin regulatory proteins, FoxA1 and GATA3, are mutated in primary ER+ disease. Finally we have discovered three previously unknown phosphorylation events on FoxA1. Aim 1: We will comprehensively explore the cross-talk that exists between ER and PR and AR pathways to determine the physiological effects on ER function. Aim 2: We will recapitulate the key mutations observed in ER, FoxA1 and GATA3, to assess the impact on ER-DNA interactions, ER transcriptional activity and cell growth and drug response. This will be explored under different hormonal contexts to identify how the mutational spectrum influences the cross-talk between ER and the parallel PR and AR pathways. Aim 3: We will identify upstream kinase pathways that influence FoxA1 and GATA3 function. Aim 4: We will establish a novel single locus chromatin purification method for isolation of specific chromatin loci, followed by Mass Spectrometry to characterise the potential role of PR and AR variants and to identify unknown regulatory factors. Given recent biological discoveries and technological advances, we are perfectly positioned to apply cutting-edge tools to glean mechanistic insight into the factors that determine variability within ER+ disease. This proposal aims to advance our understanding of ER+ tumour heterogeneity, revealing ways of exploiting this in a clinically meaningful manner. Campo scientifico medical and health sciencesclinical medicineoncologyprostate cancernatural sciencesbiological sciencesgeneticsDNAmedical and health sciencesclinical medicineoncologybreast cancernatural sciencesbiological sciencesgeneticsmutationnatural scienceschemical sciencesanalytical chemistrymass spectrometry Programma(i) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Argomento(i) ERC-CoG-2014 - ERC Consolidator Grant Invito a presentare proposte ERC-2014-CoG Vedi altri progetti per questo bando Meccanismo di finanziamento ERC-COG - Consolidator Grant Istituzione ospitante THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE Contribution nette de l'UE € 1 987 273,75 Indirizzo TRINITY LANE THE OLD SCHOOLS CB2 1TN Cambridge Regno Unito Mostra sulla mappa Regione East of England East Anglia Cambridgeshire CC Tipo di attività Higher or Secondary Education Establishments Collegamenti Contatta l’organizzazione Opens in new window Sito web Opens in new window Partecipazione a programmi di R&I dell'UE Opens in new window Rete di collaborazione HORIZON Opens in new window Costo totale € 1 987 273,75 Beneficiari (1) Classifica in ordine alfabetico Classifica per Contributo netto dell'UE Espandi tutto Riduci tutto THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE Regno Unito Contribution nette de l'UE € 1 987 273,75 Indirizzo TRINITY LANE THE OLD SCHOOLS CB2 1TN Cambridge Mostra sulla mappa Regione East of England East Anglia Cambridgeshire CC Tipo di attività Higher or Secondary Education Establishments Collegamenti Contatta l’organizzazione Opens in new window Sito web Opens in new window Partecipazione a programmi di R&I dell'UE Opens in new window Rete di collaborazione HORIZON Opens in new window Costo totale € 1 987 273,75
