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. 2019 May 14;38(1):195.
doi: 10.1186/s13046-019-1206-z.

STAT3 as a Potential Therapeutic Target in Triple Negative Breast Cancer: A Systematic Review

Free PMC article

STAT3 as a Potential Therapeutic Target in Triple Negative Breast Cancer: A Systematic Review

Jiang-Jiang Qin et al. J Exp Clin Cancer Res. .
Free PMC article


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.

Keywords: Immune escape; Oncogene; STAT3; Small molecule inhibitors; Triple negative breast cancer.

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Fig. 1
Fig. 1
The STAT3 signaling pathway in cancer cells. Under normal physiological conditions, STAT3 activation is strictly controlled by the endogenous inhibitors, including the protein inhibitor of activated STAT (PIAS), the suppressor of cytokine signaling (SOCS), and several protein tyrosine phosphatases (PTPs). Once the upstream cytokines (e.g., IL-6) or growth factors (e.g., EGF, FGF, and VEGF) bind to cell surface receptors, STAT3 is phosphorylated and activated by JAK or Src. The nonreceptor tyrosine kinases (e.g., Src and Abl) also phosphorylate STAT3. The phosphorylated STAT3 undergoes dimerization and translocates from cytoplasm into the nucleus. The activated STAT3 further binds to DNA and its coactivators (e.g., NCOA, APE, and CBP) and induces the transcription of its downstream target genes
Fig. 2
Fig. 2
Activation of STAT3 signaling promotes growth, metastasis, chemoresistance, immune escape, and stemness in TNBC. One the upstream regulators are activated, STAT3 is phosphorylated, dimerized, and translocated into the nucleus, where it activates the transcription of the target genes that regulate cell proliferation, anti-apoptosis, migration, invasion, angiogenesis, chemoresistance, immune escape, stem cell phenotypes, and autophagy
Fig. 3
Fig. 3
Inhibiting STAT3 signaling at multiple levels for cancer therapy. Currently, the majority of STAT3 inhibitors have been developed through (1) targeting the upstream regulators of STAT3, (2) binding to the SH2 domain of STAT3 and inhibiting its activation, (3) inhibiting STAT3 phosphorylation or acetylation, or (4) blocking STAT3-DNA binding. Other potential strategies, such as (5) inhibiting the binding of STAT3 with its co-activators, (6) modulating the binding of STAT3 with other interactive proteins, and (7) promoting STAT3 ubiquitination and proteasomal degradation may also be evaluated for developing novel STAT3 inhibitors

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