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01-09-2014 | Preclinical study

Phosphorylation of activating transcription factor-2 (ATF-2) within the activation domain is a key determinant of sensitivity to tamoxifen in breast cancer

Authors: Bharath Rudraraju, Marjolein Droog, Tarek M. A. Abdel-Fatah, Wilbert Zwart, Athina Giannoudis, Mohammed I. Malki, David Moore, Hetal Patel, Jacqui Shaw, Ian O. Ellis, Steve Chan, Greg N. Brooke, Ekaterina Nevedomskaya, Christiana Lo Nigro, Jason Carroll, R. Charles Coombes, Charlotte Bevan, Simak Ali, Carlo Palmieri

Published in: Breast Cancer Research and Treatment | Issue 2/2014

Abstract

Activating transcription factor-2 (ATF-2) has been implicated as a tumour suppressor in breast cancer (BC). c-JUN N-terminal kinase (JNK) and p38 MAPK phosphorylate ATF-2 within the activation domain (AD), which is required for its transcriptional activity. To date, the role of ATF-2 in determining response to endocrine therapy has not been explored. Effects of ATF-2 loss in the oestrogen receptor (ER)-positive luminal BC cell line MCF7 were explored, as well as its role in response to tamoxifen treatment. Genome-wide chromatin binding patterns of ATF-2 when phosphorylated within the AD in MCF-7 cells were determined using ChIP-seq. The expression of ATF-2 and phosphorylated ATF-2 (pATF-2-Thr71) was determined in a series of 1,650 BC patients and correlated with clinico-pathological features and clinical outcome. Loss of ATF-2 diminished the growth-inhibitory effects of tamoxifen, while tamoxifen treatment induced ATF-2 phosphorylation within the AD, to regulate the expression of a set of 227 genes for proximal phospho-ATF-2 binding, involved in cell development, assembly and survival. Low expression of both ATF-2 and pATF-2-Thr71 was significantly associated with aggressive pathological features. Furthermore, pATF-2 was associated with both p-p38 and pJNK1/2 (< 0.0001). While expression of ATF-2 is not associated with outcome, pATF-2 is associated with longer disease-free (p = 0.002) and BC-specific survival in patients exposed to tamoxifen (p = 0.01). Furthermore, multivariate analysis confirmed pATF-2-Thr71 as an independent prognostic factor. ATF-2 is important for modulating the effect of tamoxifen and phosphorylation of ATF-2 within the AD at Thr71 predicts for improved outcome for ER-positive BC receiving tamoxifen.

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Title: Phosphorylation of activating transcription factor-2 (ATF-2) within the activation domain is a key determinant of sensitivity to tamoxifen in breast cancer
Authors: Bharath Rudraraju
Marjolein Droog
Tarek M. A. Abdel-Fatah
Wilbert Zwart
Athina Giannoudis
Mohammed I. Malki
David Moore
Hetal Patel
Jacqui Shaw
Ian O. Ellis
Steve Chan
Greg N. Brooke
Ekaterina Nevedomskaya
Christiana Lo Nigro
Jason Carroll
R. Charles Coombes
Charlotte Bevan
Simak Ali
Carlo Palmieri
Publication date: 01-09-2014
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 2/2014
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-014-3098-0

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