title: Phosphorylation of activating transcription factor-2 (ATF-2) within the activation domain is a key determinant of sensitivity to tamoxifen in breast cancer.
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.
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, The Duncan Building, Daulby Street, Liverpool, L69 3GA, UK.
authors.forename: Bharath
authors.initials: B
authors.lastname: Rudraraju
authors.forename: Marjolein
authors.initials: M
authors.lastname: Droog
authors.forename: Tarek M A
authors.initials: TM
authors.lastname: Abdel-Fatah
authors.forename: Wilbert
authors.initials: W
authors.lastname: Zwart
authors.forename: Athina
authors.initials: A
authors.lastname: Giannoudis
authors.forename: Mohammed I
authors.initials: MI
authors.lastname: Malki
authors.forename: David
authors.initials: D
authors.lastname: Moore
authors.forename: Hetal
authors.initials: H
authors.lastname: Patel
authors.forename: Jacqui
authors.initials: J
authors.lastname: Shaw
authors.forename: Ian O
authors.initials: IO
authors.lastname: Ellis
authors.forename: Steve
authors.initials: S
authors.lastname: Chan
authors.forename: Greg N
authors.initials: GN
authors.lastname: Brooke
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Nevedomskaya
authors.forename: Christiana
authors.initials: C
authors.lastname: Lo Nigro
authors.forename: Jason
authors.initials: J
authors.lastname: Carroll
authors.forename: R Charles
authors.initials: RC
authors.lastname: Coombes
authors.forename: Charlotte
authors.initials: C
authors.lastname: Bevan
authors.forename: Simak
authors.initials: S
authors.lastname: Ali
authors.forename: Carlo
authors.initials: C
authors.lastname: Palmieri
mesh_terms: D051698:Activating Transcription Factor 2 / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D061986:MCF-7 Cells; D010766:Phosphorylation; D011379:Prognosis; D013629:Tamoxifen / Q000494:pharmacology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; D004268:DNA-Binding Proteins; D014157:Transcription Factors; D013629:Tamoxifen; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases