Rudraraju, Bharath and Droog, Marjolein and Abdel-Fatah, Tarek MA and Zwart, Wilbert and Giannoudis, Athina and Malki, Mohammed I and Moore, David and Patel, Hetal and Shaw, Jacqui and Ellis, Ian O and Chan, Steve and Brooke, Greg N and Nevedomskaya, Ekaterina and Nigro, Christiana Lo and Carroll, Jason and Coombes, R Charles and Bevan, Charlotte and Ali, Simak and Palmieri, Carlo (2014) Phosphorylation of activating transcription factor-2 (ATF-2) within the activation domain is a key determinant of sensitivity to tamoxifen in breast cancer. Breast Cancer Research and Treatment, 147 (2). pp. 295-309. DOI https://doi.org/10.1007/s10549-014-3098-0
Rudraraju, Bharath and Droog, Marjolein and Abdel-Fatah, Tarek MA and Zwart, Wilbert and Giannoudis, Athina and Malki, Mohammed I and Moore, David and Patel, Hetal and Shaw, Jacqui and Ellis, Ian O and Chan, Steve and Brooke, Greg N and Nevedomskaya, Ekaterina and Nigro, Christiana Lo and Carroll, Jason and Coombes, R Charles and Bevan, Charlotte and Ali, Simak and Palmieri, Carlo (2014) Phosphorylation of activating transcription factor-2 (ATF-2) within the activation domain is a key determinant of sensitivity to tamoxifen in breast cancer. Breast Cancer Research and Treatment, 147 (2). pp. 295-309. DOI https://doi.org/10.1007/s10549-014-3098-0
Rudraraju, Bharath and Droog, Marjolein and Abdel-Fatah, Tarek MA and Zwart, Wilbert and Giannoudis, Athina and Malki, Mohammed I and Moore, David and Patel, Hetal and Shaw, Jacqui and Ellis, Ian O and Chan, Steve and Brooke, Greg N and Nevedomskaya, Ekaterina and Nigro, Christiana Lo and Carroll, Jason and Coombes, R Charles and Bevan, Charlotte and Ali, Simak and Palmieri, Carlo (2014) Phosphorylation of activating transcription factor-2 (ATF-2) within the activation domain is a key determinant of sensitivity to tamoxifen in breast cancer. Breast Cancer Research and Treatment, 147 (2). pp. 295-309. DOI https://doi.org/10.1007/s10549-014-3098-0
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.
Item Type: | Article |
---|---|
Uncontrolled Keywords: | Breast cancer; Activating transcription; factor-2; Phosphorylation; Tamoxifen |
Subjects: | R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) |
Divisions: | Faculty of Science and Health Faculty of Science and Health > Life Sciences, School of |
SWORD Depositor: | Unnamed user with email elements@essex.ac.uk |
Depositing User: | Unnamed user with email elements@essex.ac.uk |
Date Deposited: | 09 Feb 2015 12:20 |
Last Modified: | 30 Oct 2024 19:51 |
URI: | http://repository.essex.ac.uk/id/eprint/12730 |