Emerging roles of activating transcription factor 2 in the development of breast cancer: a comprehensive review

Abstract

Activating transcription factor 2 (ATF2) is a member of the leucine zipper family of DNA binding proteins that are responsible for regulating various genes that play an essential role in major biological and cellular functions. Since ATF2 plays a vital role in cellular proliferation and apoptosis, it is believed that it greatly affects the development of breast cancers. However, its exact role in breast cancer is incompletely understood. It remains a subject of debate, ambiguity, and continuous research. Several studies have suggested the role of ATF2 as an oncogene, promoting cellular proliferation and worsening the outcome of cancers. In contrast, other studies have postulated that ATF2 plays a tumor suppressive role in estrogen receptor-positive breast cancer. The ambiguity surrounding its role in breast cancer is the reason why there is an influx of recent studies and research in this area. In this narrative review, we investigate several studies that have been published about the role of ATF2 in breast cancer. We also explore studies that have examined the association between ATF2 and endocrine therapy resistance. ATF2 has been suggested to modulate estrogen receptor (ER) expression and activity, potentially affecting tamoxifen sensitivity in breast cancer cells. Therefore, the role of ATF2 in DNA repair mechanisms and drug resistance has been deeply explored in this review. Additionally, there are numerous ongoing clinical trials exploring the effect of targeting ATF2 pathways and mechanisms on the outcome of breast cancers, some of which we have discussed. The studies and clinical trials that are being conducted to understand the multifaceted role of ATF2 and its signaling pathways may provide valuable insight for developing efficient targeted therapeutic solutions to enhance the outcomes of breast cancer and overcome endocrine resistance. We suggest further research to elucidate the dual roles of ATF2 in breast cancer and potential therapeutic therapies for its treatment.

Keywords: ATF2; breast cancer; oncogene.

Figure 1.

An illustration showing the ERK1/ATF2 pathway that upregulates MMP3 leading to several cellular effects. TF, transcription factors.

Figure 2.

An illustration depicting the phosphorylation of ATF2 activation domains by phosphorylating factors and the consequent actions of ATF2 on gene transcription. p38, p38 MAPK.

Figure 3.

An illustration showing how the JIP complex is activated by stress signalling molecules (including ASK1, MAP2k7, and JNK), inducing the activation of ATF2 and C-JUN, which was shown to increase cellular mechanisms like chemoresistance, cell growth, and multiplication, which may enhance tumor progression. JIP, JNK-interacting protein; MAP2k7, mitogen-activated protein kinase; ASK1, apoptosis signal-regulating kinase 1.