STAT3: Key targets of growth-promoting receptor positive breast cancer

Abstract

Breast cancer has become the malignant tumor with the first incidence and the second mortality among female cancers. Most female breast cancers belong to luminal-type breast cancer and HER2-positive breast cancer. These breast cancer cells all have different driving genes, which constantly promote the proliferation and metastasis of breast cancer cells. Signal transducer and activator of transcription 3 (STAT3) is an important breast cancer-related gene, which can promote the progress of breast cancer. It has been proved in clinical and basic research that over-expressed and constitutively activated STAT3 is involved in the progress, proliferation, metastasis and chemotherapy resistance of breast cancer. STAT3 is an important key target in luminal-type breast cancer and HER2-positive cancer, which has an important impact on the curative effect of related treatments. In breast cancer, the activation of STAT3 will change the spatial position of STAT3 protein and cause different phenotypic changes of breast cancer cells. In the current basic research and clinical research, small molecule inhibitors activated by targeting STAT3 can effectively treat breast cancer, and enhance the efficacy level of related treatment methods for luminal-type and HER2-positive breast cancers.

Keywords: Breast cancer; Cell growth; Growth-promoting; Oncogene; STAT3; Small molecule inhibitors.

Fig. 1

Schematic diagram of STAT3 protein structure. Schematics of STAT3 protein structure and function. A The STAT3 protein structure includes an N-segment domain, helix-helix domain, DNA binding domain, linker, Src homology 2 domain, and C-segment domain. The DNA-binding domain of the STAT3 protein is primarily responsible for DNA transcription, while the Src homology domain is primarily responsible for promoting STAT3 protein dimerization. These domains are regulated by the phosphorylation level of Y705 and S727 sites. B The three-dimensional structure diagram of STAT3 protein promotes it's role in DNA binding, dimerization, and reverse transcription

Fig. 2

Main STAT3 signal transduction pathways in breast cancer. STAT3 is an essential regulatory protein in breast cancer. A IL-6 (EGFR)/STAT3 signaling regulates breast cancer proliferation, invasion, anti-apoptosis, and other malignant biological behaviors. The occurrence of these phenotypes depends on the overactivation of STAT3. B The effects of different upstream receptors on the activation of the STAT3 signaling pathway and the regulation of STAT3 by other proteins in different cellular localizations

Fig. 3

Regulation of STAT3 in HER2-positive breast cancer. In HER2-positive breast cancer, STAT3 is activated through the EGFR/Src and IL-6/JAK pathways. This leads to abnormally high-level expression of STAT3 in HER2-positive breast cancer. Currently, HER2 inhibitors (trastuzumab, pertuzumab, and lapatinib) are primarily used to treat HER2-positive breast cancer. These drugs can block STAT3 activated by the EGFR/Src pathway but cannot inhibit STAT3 activated by IL-6/JAK pathway. The sustained high level of STAT3 expression also enhances the resistance of HER2-positive breast cancer cells to HER2 treatment

Fig. 4

Regulation of STAT3 on basic hallmarks of tumors. Schematic of the regulatory effect of STAT3 on cancer markers. Cancer has 14 basic characteristics, and STAT3 has an essential influence on 13 of these (maintaining proliferation signal, evolving growth inhibitory factor, deregulating cell metabolism, avoiding immune damage, resisting cell death, achieving immortal reproduction, genome instability and mutation, tumor-promoting inflammation, inducing or approaching blood vessels, activating invasion and metastasis, unlocking phenotypic plasticity, non-mutant epigenetic reprogramming, and aging cells)

Fig. 5

Schematic diagram of action mechanism of STAT3 direct inhibitor. Presently, the treatment strategy for STAT3 inhibitors in breast cancer mainly involves inhibiting the biological function of STAT3 protein directly or by inhibiting the mRNA level of STAT3 protein. A Direct inhibitors of STAT3 mainly target the SH2 or DBD binding domains of STAT3. These inhibitors can inhibit STAT3 transcription by inhibiting STAT3 dimerization or it's binding to DNA. B Some PROTAC drugs (SD-36) mainly degrade STAT3 protein, thus reducing it's expression levels [196]