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

Qin, Jiang‐Jiang; Li, Yan; Zhang, Jia; Zhang, Weidong

doi:10.1186/s13046-019-1206-z

Cited by 260 publications

(197 citation statements)

References 147 publications

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“…Reducing GR activity by decreasing amounts of dexamethasone resulted in decreased cell growth in a dose-dependent manner (Figure 7B). These results are consistent with previous publications that report that inhibiting GR or STAT3 separately decreases basal-like breast cancer proliferation (18,(46)(47)(48).…”

Section: Inhibiting Both Gr and Stat3 Reduces Cell Proliferation Synesupporting

confidence: 94%

“…While GR and STAT3 have been separately implicated in regulating gene expression in basal-like breast cancer previously (18,48,51,52), their cooperative role has not been previously described. This study makes it apparent that understanding this cooperation is crucial to investigating their roles in driving basal-like TNBC gene expression and phenotypes, as well as arriving at more effective therapeutic strategies.…”

Section: Discussionmentioning

confidence: 99%

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STAT3 and GR cooperate to drive basal-like triple negative breast cancer gene expression and proliferation

Conway

McDaniel

Graham

et al. 2019

Preprint

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Breast cancers can be divided into subtypes with different prognoses and treatment responses based on global gene expression differences. Luminal breast cancer gene expression and proliferation are driven by the transcription factors Estrogen Receptor a (ER), FOXA1 and GATA3. Targeting ER is the most effective therapy for treating luminal breast cancer because ER is the master regulator of the luminal gene expression program.In contrast, it is unclear which transcription factors are responsible for driving the gene expression signature that defines basal-like triple negative breast cancer, and there are no targeted therapies approved to treat this aggressive subtype of the disease. This study utilized integrated analysis of DNA methylation, chromatin accessibility, transcription factor binding, and gene expression in large collections of breast cancer cell lines and patient tumors to identify transcription factors responsible for the basal-like gene expression program. The results of this study indicate that glucocorticoid receptor (GR) and signal transducer and activator of transcription 3 (STAT3) bind to the same genomic regulatory regions that are specifically open and unmethylated in basal-like breast cancer. These transcription factors cooperate to regulate expression of hundreds of genes in the basallike gene expression signature and these downstream genes are associated with poor prognosis in patients.Furthermore, combination treatment with small molecule drugs that inhibit both transcription factors leads to synergistic decreases in cell proliferation in cell lines and patient-derived organoid models. This study demonstrates that GR and STAT3 cooperate to regulate the basal-like breast cancer gene expression program and provides the basis for improved therapy for basal-like triple negative breast cancer through rational combination of STAT3 and GR inhibitors.) in the chromatin regions that were specifically open in basal-like tumors and closed in luminal tumors ( Figure 1E). While the enrichment for the GR motif is significant, it is lower than that of STAT3 and JUN/AP1, which is consistent with previous studies that suggest GR can be tethered to some enhancers through protein:protein interactions, rather than direct DNA binding(30). MEC, JMM, JMG, KPG, PGO, and SLP performed experiments. MEC and KEV performed analysis and wrote the manuscript. PY and JT provided reagents. DJB, BEW, and RMM provided expertise and feedback.

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Section: Inhibiting Both Gr and Stat3 Reduces Cell Proliferation Synesupporting

confidence: 94%

Section: Discussionmentioning

confidence: 99%

STAT3 and GR cooperate to drive basal-like triple negative breast cancer gene expression and proliferation

Conway

McDaniel

Graham

et al. 2019

Preprint

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“…In contrast to rapamycin, which did not totally suppress STAT3 phosphorylation, the STAT3 inhibitor, S3I‐201, strongly suppressed STAT‐3 activation after IL‐6 stimulation. Although S31‐201 is not a clinically applicable drug, there are several STAT3 inhibitors that have entered clinical trials as potential cancer therapy . IL‐6 upregulated expression of VEGF and FGF2 mRNA in pAECs.…”

Section: Discussionmentioning

confidence: 99%

“…Although S31-201 is not a clinically applicable drug, there are several STAT3 inhibitors that have entered clinical trials as potential cancer therapy. 46 IL-6 upregulated expression of VEGF and FGF2 mRNA in pAECs. It has been reported that IL-6…”

Section: F I G U R Ementioning

confidence: 99%

Is interleukin-6 receptor blockade (tocilizumab) beneficial or detrimental to pig-to-baboon organ xenotransplantation?

Zhang

Iwase

Wang

et al. 2020

American Journal of Transplantation

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The interleukin (IL)‐6/IL‐6 receptor‐α (IL‐6Rα)/signal transduction and activation of the transcription 3 (STAT3) pathway plays an important role in inflammation. Anti‐human IL‐6Rα blockade by tocilizumab (TCZ) has been used in pig‐to‐baboon organ xenotransplant models, but whether it is beneficial remains uncertain. After xenotransplant, there were significant increases in both baboon and pig IL‐6 in the baboon serum, especially in baboons that received TCZ before xenotransplant. In vitro observations demonstrated that human, baboon, and pig IL‐6 can activate the IL‐6/IL‐6Rα/STAT3 pathway in human, baboon, and pig cells, respectively. Activation of the IL‐6/IL‐6Rα/STAT3 pathway was blocked by TCZ in human and baboon cells but not in pig cells (ie, pig IL‐6R). Siltuximab (human IL‐6 inhibitor) bound to both human and baboon, but not pig, IL‐6 and suppressed activation of the IL‐6/IL‐6Rα/STAT3 pathway. These results indicate that TCZ and siltuximab do not cross‐react with pig IL‐6R and pig IL‐6, respectively. Rapamycin partially inhibited human, baboon, and pig IL‐6/IL‐6Rα/STAT3 pathways and suppressed inflammatory gene expression. TCZ treatment increased serum IL‐6 because it could no longer bind to baboon IL‐6Rα. We suggest that increased serum IL‐6 may be detrimental to the pig xenograft because it is likely to bind to pig IL‐6R, resulting in activation of pig cells.

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“…the STAT3 inhibitors AZD9150 in non-Hodgkin's lymphoma, OPB-51602 in nonsmall-cell lung cancer and napabucasin in advanced colorectal cancer, and the STAT5 inhibitor pioglitazone (added to imatinib) in chronic myeloid leukaemia. [10][11][12][13][14][15] The role of STATs in the human epithelial carcinogenesis has been poorly investigated, but in the era of studies on inhibitors targeting STAT proteins, this topic seems to be worth exploring. Chan et al reported that Stat3 in mice is required for de novo epithelial carcinogenesis, showing that Stat3 is involved in both initiation and promotion of carcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

STAT 3, STAT 5A, STAT 5B and STAT 6 proteins are overexpressed in human basal cell carcinoma

et al. 2019

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Summary Background The molecular pathogenesis of basal cell carcinoma (BCC) is still not precisely described and is the subject of ongoing studies. The role of signal transducers and activators of transcription (STATs) in human epithelial carcinogenesis has been poorly investigated, but in the era of studies on inhibitors targeting STAT proteins this topic seems worth exploring. Increased expression of STAT3 in human nonmelanoma skin cancer (NMSC) has been confirmed in a few studies, but to our knowledge, expression of STAT5A, STAT5B and STAT6 in BCC has not been previously evaluated. Aim To measure expression of STAT3, STAT5A, STAT5B and STAT6 expression in different histopathological subtypes of human BCC and its correlation with selected clinical variables. Methods Immunohistochemistry was used to assess 60 BCC tumour specimens [20 superficial (s)BCCs, 20 nodular (n)BCCs and 20 infiltrative (i)BCCs] and to compare with specimens of healthy skin. There was no significant difference in age or sex between the three groups of patients with BCC. As many tumours showed heterogeneity of staining, the H‐score system was applied to calculate the intensity of immunoexpression. Results Expression of STAT3, STAT5A, STAT5B and STAT6 was observed in all histopathological subtypes of BCC, and was stronger than the expression within the adjacent epidermis and also stronger than the expression within the epidermis in the healthy control group. Statistical analysis revealed no significant differences in mean H‐scores calculated for sBCCs, nBCCs and iBCCs. There were no statistically significant associations between STAT3, STAT5A, STAT5B and STAT6 expression and patient sex/age, and tumour size/site. Conclusion Our results confirm a possible role of STATs in the pathogenesis of BCC and should encourage future investigations on the possible therapeutic implications of this finding.

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

Cited by 260 publications

References 147 publications

STAT3 and GR cooperate to drive basal-like triple negative breast cancer gene expression and proliferation

STAT3 and GR cooperate to drive basal-like triple negative breast cancer gene expression and proliferation

Is interleukin-6 receptor blockade (tocilizumab) beneficial or detrimental to pig-to-baboon organ xenotransplantation?

STAT 3, STAT 5A, STAT 5B and STAT 6 proteins are overexpressed in human basal cell carcinoma

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