Phosphorylation of activating transcription factor-2 (ATF-2) within the activation domain is a key determinant of sensitivity to tamoxifen in breast cancer
- 648 Downloads
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.
KeywordsBreast cancer Activating transcription factor-2 Phosphorylation Tamoxifen
Carlo Palmieri was supported by a clinician scientist fellowship from Cancer Research UK, Wilbert Zwart by a KWF Dutch Cancer Society Fellowship and a VENI scholarship from the Dutch Organisation for Scientific Research NWO, and Jason Carroll by an ERC starting grant and an EMBO Young investigator award. We thank Angie Gillies (University of Leicester) for technical help with immunohistochemistry. We would also like to acknowledge the support of Cancer Research UK Cambridge Research Institute, The Netherlands Cancer Institute and A Sisters Hope. The Department of Molecular and Clinical Cancer Medicine forms part of the North West Cancer Centre-University of Liverpool which is funded by North West Cancer Research. Research support is also received from The Clatterbridge Cancer Charity.
Conflict of Interest
The authors declare no conflict of interest.
- 17.Ouwens DM, de Ruiter ND, van der Zon GC, Carter AP, Schouten J, van der Burgt C, Kooistra K, Bos JL, Maassen JA, van Dam H (2002) Growth factors can activate ATF2 via a two-step mechanism: phosphorylation of Thr71 through the Ras-MEK-ERK pathway and of Thr69 through RalGDS-Src-p38. EMBO J 21:3782–3793PubMedCentralPubMedCrossRefGoogle Scholar
- 31.Lopez-Garcia J, Periyasamy M, Thomas RS, Christian M, Leao M, Jat P, Kindle KB, Heery DM, Parker MG, Buluwela L, Kamalati T, Ali S (2006) ZNF366 is an estrogen receptor corepressor that acts through CtBP and histone deacetylases. Nucleic Acids Res 34:6126–6136PubMedCentralPubMedCrossRefGoogle Scholar
- 33.Loi S, Haibe-Kains B, Desmedt C, Lallemand F, Tutt AM, Gillet C, Ellis P, Harris A, Bergh J, Foekens JA, Klijn JG, Larsimont D, Buyse M, Bontempi G, Delorenzi M, Piccart MJ, Sotiriou C (2007) Definition of clinically distinct molecular subtypes in estrogen receptor-positive breast carcinomas through genomic grade. J Clin Oncol 25:1239–1246PubMedCrossRefGoogle Scholar
- 34.Wang Y, Klijn JG, Zhang Y, Sieuwerts AM, Look MP, Yang F, Talantov D, Timmermans M, Meijer-van Gelder ME, Yu J, Jatkoe T, Berns EM, Atkins D, Foekens JA (2005) Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer. Lancet 365:671–679PubMedCrossRefGoogle Scholar
- 36.Abdel-Fatah TM, Perry C, Dickinson P, Ball G, Moseley P, Madhusudan S, Ellis IO, Chan SY (2013) Bcl2 is an independent prognostic marker of triple negative breast cancer (TNBC) and predicts response to anthracycline combination (ATC) chemotherapy (CT) in adjuvant and neoadjuvant settings. Ann Oncol 11:2801–2807CrossRefGoogle Scholar
- 40.Choi JH, Cho HK, Choi YH, Cheong J (2009) Activating transcription factor 2 increases transactivation and protein stability of hypoxia-inducible factor 1alpha in hepatocytes. Biochem J 42:4285–4296Google Scholar
- 45.Mynard V, Latchoumanin O, Guignat L, Devin-Leclerc J, Bertagna X, Barré B, Fagart J, Coqueret O, Catelli MG (2004) Synergistic signaling by corticotropin-releasing hormone and leukemia inhibitory factor bridged by phosphorylated 3′,5′-cyclic adenosine monophosphate response element binding protein at the Nur response element (NurRE)-signal transducers and activators of transcription (STAT) element of the proopiomelanocortin promoter. Mol Endocrinol 18:2997–3010PubMedCrossRefGoogle Scholar