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ER_disease SIGNED

Defining hormonal cross-talk and the role of mutations in estrogen receptor positive breast cancer

Total Cost €

EC-Contrib. €

Partnership

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Outcomes and
results

ER_disease project word cloud

Explore the words cloud of the ER_disease project. It provides you a very rough idea of what is the project "ER_disease" about.

mutated positioned purification driving unknown androgen uncharacterised routinely locus proteins talk characterise technological spectrometry ways discoveries manner loci biological exists explaining variants breast expressed discovered previously influence perfectly mutations drug transcriptional foxa1 receptor hormonal events mass interactions regulatory 55 pr gata3 heterogeneity cutting parallel 18 edge physiological function estrogen variability shown progesterone tools influences clinical contexts dna phosphorylation mechanistic clinically comprehensively explore recapitulate tumour ar treatment mutational revealing disease primary glean explored followed metastatic antagonists cross 75 transcription isolation cancers er tumours spectrum single chromatin kinase cell upstream

Project "ER_disease" data sheet

The following table provides information about the project.

Coordinator	THE CHANCELLOR MASTERS AND SCHOLARSOF THE UNIVERSITY OF CAMBRIDGE Organization address address: TRINITY LANE THE OLD SCHOOLS city: CAMBRIDGE postcode: CB2 1TN website: www.cam.ac.uk contact info title: n.a. name: n.a. surname: n.a. function: n.a. email: n.a. telephone: n.a. fax: n.a.
Coordinator Country	United Kingdom [UK]
Total cost	1˙987˙273 €
EC max contribution	1˙987˙273 € (100%)
Programme	1. H2020-EU.1.1. (EXCELLENT SCIENCE - European Research Council (ERC))
Code Call	ERC-2014-CoG
Funding Scheme	ERC-COG
Starting year	2015
Duration (year-month-day)	from 2015-06-01 to 2020-05-31

Partnership

Take a look of project's partnership.

#	participants	country	role	EC contrib. [€]
1	THE CHANCELLOR MASTERS AND SCHOLARSOF THE UNIVERSITY OF CAMBRIDGE THE CHANCELLOR MASTERS AND SCHOLARSOF THE UNIVERSITY OF CAMBRIDGE Organization address address: TRINITY LANE THE OLD SCHOOLS city: CAMBRIDGE postcode: CB2 1TN website: www.cam.ac.uk contact info title: n.a. name: n.a. surname: n.a. function: n.a. email: n.a. telephone: n.a. fax: n.a.	UK (CAMBRIDGE)	coordinator	1˙987˙273.00

Map

Project objective

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.

Publications

List of publications.
year	authors and title	journal	last update
2020	Sankari Nagarajan, Shalini V. Rao, Joseph Sutton, Danya Cheeseman, Shanade Dunn, Evangelia K. Papachristou, Jose-Enrique Gonzalez Prada, Dominique-Laurent Couturier, Sanjeev Kumar, Kamal Kishore, Chandra Sekhar Reddy Chilamakuri, Silvia-Elena Glont, Emily Archer Goode, Cara Brodie, Naomi Guppy, Rachael Natrajan, Alejandra Bruna, Carlos Caldas, Alasdair Russell, Rasmus SiersbÃ¦k, Kosuke Yusa, Igor ARID1A influences HDAC1/BRD4 activity, intrinsic proliferative capacity and breast cancer treatment response published pages: , ISSN: 1061-4036, DOI: 10.1038/s41588-019-0541-5	Nature Genetics	2020-02-04
2019	Silvia-E. Glont, Igor Chernukhin, Jason S. Carroll Comprehensive Genomic Analysis Reveals that the Pioneering Function of FOXA1 Is Independent of Hormonal Signaling published pages: 2558-2565.e3, ISSN: 2211-1247, DOI: 10.1016/j.celrep.2019.02.036	Cell Reports 26/10	2020-02-04
2018	A. A. Serandour, H. Mohammed, A. Miremadi, K. W. Mulder, J. S. Carroll TRPS1 regulates oestrogen receptor binding and histone acetylation at enhancers published pages: , ISSN: 0950-9232, DOI: 10.1038/s41388-018-0312-2	Oncogene	2020-01-21
2016	Jason S. Carroll, Theresa E. Hickey, Gerard A. Tarulli, Michael Williams, Wayne D. Tilley Deciphering the divergent roles of progestogens in breast cancer published pages: 54-64, ISSN: 1474-175X, DOI: 10.1038/nrc.2016.116	Nature Reviews Cancer 17/1	2020-01-21
2018	Evangelia K. Papachristou, Kamal Kishore, Andrew N. Holding, Kate Harvey, Theodoros I. Roumeliotis, Chandra Sekhar Reddy Chilamakuri, Soleilmane Omarjee, Kee Ming Chia, Alex Swarbrick, Elgene Lim, Florian Markowetz, Matthew Eldridge, Rasmus Siersbaek, Clive S. Dâ€™Santos, Jason S. Carroll A quantitative mass spectrometry-based approach to monitor the dynamics of endogenous chromatin-associated protein complexes published pages: , ISSN: 2041-1723, DOI: 10.1038/s41467-018-04619-5	Nature Communications 9/1	2020-01-21
2016	Kamila M. Jozwik, Igor Chernukhin, Aurelien A. Serandour, Sankari Nagarajan, Jason S. Carroll FOXA1 Directs H3K4 Monomethylation at Enhancers via Recruitment of the Methyltransferase MLL3 published pages: 2715-2723, ISSN: 2211-1247, DOI: 10.1016/j.celrep.2016.11.028	Cell Reports 17/10	2020-01-21
2017	Adam W. Nelson, Arnoud J. Groen, Jodi L. Miller, Anne Y. Warren, Kelly A. Holmes, Gerard A. Tarulli, Wayne D. Tilley, Benita S. Katzenellenbogen, John R. Hawse, Vincent J. Gnanapragasam, Jason S. Carroll Comprehensive assessment of estrogen receptor beta antibodies in cancer cell line models and tissue reveals critical limitations in reagent specificity published pages: 138-150, ISSN: 0303-7207, DOI: 10.1016/j.mce.2016.11.016	Molecular and Cellular Endocrinology 440	2020-01-21

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