Abstract P3-06-13: Expression of Phosphorylated Activating Transcription factor 2 (ATF2) is associated with sensitivity to endocrine therapy in breast cancer
Authors: Palmieri C , Rudraraju B , Abdel-Fatah TMA , Moore DA , Shaw J , Green A , Ellis IO , Coombes RC , Simak A 
Published: August 2014

Abstract
Background: The Activating Transcription Factor 2 (ATF2) gene is a member of the ATF and CREB group of bZIP transcription factors. It is involved in in transcriptional control, chromatin remodelling and the DNA damage response. Two threonine residues (Thr69 and Thr71) within the activation domain (AD) are important for its transcriptional activation and high pThr69/pThr71-ATF2 has been correlated with a well-differentiated phenotype in breast cancer (BC). In this study the protein expression of ATF2 & pThr71-ATF2 (pATF2) and its association with clinico-pathological features and outcome in a well defined BC series were studied.
Methods: The expression of ATF2 and pATF2 was assessed in the Nottingham Tenovus Primary Breast Cancer Series which consists of 1650 cases of primary invasive BC. ATF2 and pATF2 were correlated with clinico-pathological data as well as outcome in those high risk cases (NPI&gt;3.4) based on exposure to tamoxifen.
Results: A total of 1351 tumours were suitable for analysis of both ATF2 and pATF2; 436/1351 (32%) of BC co-expressed ATF2 and pATF2 while 414/1351(31%) were negative for both ATF2 and pThr71-ATF2. Co-expression ATF2 and pATF2 was highly significantly associated luminal breast cancer phenotype, well differentiation, low proliferation (low mitotic index, low Ki67 and low SPAG5; ps&lt;0.0001), hormonal receptors, high expression of ER associated proteins (cyclin D1 and Bcl2; p &lt; 0.0001), high expression of c-jun (p &lt; 0.0001), JNK (p &lt; 0.0001), pSRC3 (p &lt; 0.0001), and active p53 transcriptional pathways that regulate cell cycle progression and apoptosis (p21+ve, MDM2+ve, MDM4+ve & Bax+ve; p &lt; 0.0001) and absence of basal like phenotypes (p &lt; 0.0001). While absence of ATF2 and pATF2 was significantly associated with loss of expression of the key DNA repair proteins including XRCC1 (p &lt; 0.0001), BRCA1 (p &lt; 0.0001), ATM (p = 0.008) and TOP2A (p &lt; 0.0001) reflecting a higher risk of genomic instability. In addition, absence of pATF2 was associated with abnormal expression of other tumour suppressor proteins such as p53 (p = 0.03), p16 (p &lt; 0.001) and FHIT (p &lt; 0.0001) and was associated with epithelial-mesenchymal transition indicator proteins (vimentin+ve, p63+ve, CK18-ve, and E-cadherin-ve). There was no association with outcome based on the expression of ATF2 either with or without tamoxifen. However, expression of pATF2 was associated with significantly longer breast cancer specific survival (HR: 0.69, 95% CI: 0.51–0.92, p = 0.01) and disease free survival (HR: 0.66, 95% CI: 0.51–0.86, p = 0.002) in patients exposed to tamoxifen; this was not observed when tamoxifen was not used in high risk ER+ ve BC.
Discussion: Coexpression of ATF2 and pATF2 is associated with a luminal phenotype and features of good prognostic disease. The absence of ATF2 and pATF2 was associated with a higher risk of genomic instability. While ATF2 had no prognostic significance, the presence of the transcriptionally active form was associated with a significant improvement in outcome in patients treated with tamoxifen, which was not observed in the absence of tamoxifen. The role of the transcriptionally active form of ATF2 warrants further investigation with regard to breast cancer and its role in modulating response to tamoxifen.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-06-13.