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.

Clinicopathological and prognostic significance of mitogen-activated protein kinases (MAPK) in breast cancers

“…Consistent with previous studies that assessed the prognostic value of individual MAPK members [ 32 , 43 , 44 ], in this study we identified an association between MAPKs proteins and better outcome in terms of longer survival time. Importantly, in the current research, pan ERK1/2 and p-ERK1/2 showed an association with better outcome in patients with ER+ tumours who are candidate for endocrine therapy.…”

“…Moreover, several studies have demonstrated the role of p-p38/MAPK in inducing apoptosis in BC and some suggested that this effect is mediated by TGF-β [ 37 – 40 ]. p-ATF2 is thought to have dual functions independent of each other; the first is a tumour suppressor protein and the other function is related to DNA damage response pathway [ 41 ] and importantly, the former function has been confirmed by different studies [ 38 , 42 , 43 ]. The above results regarding the association between MAPKs and apoptosis were supported by our findings that MAPKs were positively associated with ER, BCL2 and negatively with HER2 (or no association with some of them), KI67-LI and p53.…”

MicroRNA-Dependent Targeting of RSU1 and the IPP Adhesion Complex Regulates the PTEN/PI3K/AKT Signaling Pathway in Breast Cancer Cell Lines

“…The reduction in RSU1 by miR-182-5p and miR-409-3p in MCF10A mammary epithelial cells inhibited PTEN and the same MKK4-p38-ATF2 signaling pathway to PTEN that we previously identified. This finding may be clinically useful since the phosphorylation of ATF2 within the activation domain is a key determinant of sensitivity to tamoxifen in luminal breast cancer [67].…”

ATF2, a paradigm of the multifaceted regulation of transcription factors in biology and disease

“…For example, in contrast to the cancer types mentioned above, ATF2 appears to play a tumor suppressor role in breast cancer, where its transcriptional activity is required for sensitivity to tamoxifen-based treatments (79)—thus its inhibition would be detrimental in this context. Further studies into the specific transcriptional targets of ATF2 in discrete tumor types are warranted, as ATF2 does not play the same role in all tumors.…”