STAT3 as a potential therapeutic target in triple negative breast cancer: a systematic review

Jiang-Jiang Qin,Jia Zhang,Li Yan,Wei-Dong Zhang

doi:10.1186/s13046-019-1206-z

Abstract

Triple negative breast cancer (TNBC), which is typically lack of expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), represents the most aggressive and mortal subtype of breast cancer. Currently, only a few treatment options are available for TNBC due to the absence of molecular targets, which underscores the need for developing novel therapeutic and preventive approaches for this disease. Recent evidence from clinical trials and preclinical studies has demonstrated a pivotal role of signal transducer and activator of transcription 3 (STAT3) in the initiation, progression, metastasis, and immune evasion of TNBC. STAT3 is overexpressed and constitutively activated in TNBC cells and contributes to cell survival, proliferation, cell cycle progression, anti-apoptosis, migration, invasion, angiogenesis, chemoresistance, immunosuppression, and stem cells self-renewal and differentiation by regulating the expression of its downstream target genes. STAT3 small molecule inhibitors have been developed and shown excellent anticancer activities in in vitro and in vivo models of TNBC. This review discusses the recent advances in the understanding of STAT3, with a focus on STAT3’s oncogenic role in TNBC. The current targeting strategies and representative small molecule inhibitors of STAT3 are highlighted. We also propose potential strategies that can be further examined for developing more specific and effective inhibitors for TNBC prevention and therapy.

Highlights

Triple negative breast cancer (TNBC) is the most aggressive form of breast cancer and accounts for much higher recurrence and metastasis rates [1]
All STAT proteins consist of an amino acid domain (NH2), a coiled-coil domain (CCD) for binding with interactive proteins, a DNA binding domain (DBD), a linker domain, a SRC homology 2 (SH2) domain for phosphorylation and dimerization, and a C-terminal transactivation domain (TAD) [11]
We focus on the recent findings related to signal transducer and activator of transcription 3 (STAT3)’s role in TNBC as well as STAT3 inhibitors and current targeting strategies

Summary

Introduction

Triple negative breast cancer (TNBC) is the most aggressive form of breast cancer and accounts for much higher recurrence and metastasis rates [1]. JAK2 inhibitors, including silibinin [97] and ganoderic acid A [98] were found to inhibit TNBC cell viability, migration, and invasion and induce apoptosis in vitro through inhibiting the JAK2/STAT3 signaling pathway.

Results

Conclusion