PurposeChronic stress and related hormones are key in cancer progression. Peroxisome proliferator-activated receptor γ (PPARγ) and its agonists was reported that inducing anti-tumor effect. However, the function of PPARγ in pro-tumorigenic effects induced by chronic stress in breast cancer remains unknown. Herein, we have characterized a novel role of PPARγ and vascular endothelial growth factor (VEGF)/fibroblast growth factor 2 (FGF2) signals in breast cancer promoted by chronic stress.Materials and MethodsWe performed experiments <i>in vivo</i> and <i>in vitro</i> and used bioinformatics data to evaluate the therapeutic potential of PPARγ in breast cancer promoted by stress.ResultsChronic stress significantly inhibited the PPARγ expression and promoted breast cancer <i>in vivo</i>. VEGF/FGF2-mediated angiogenesis increased in the chronic stress group compared to the control group. PPARγ agonist pioglitazone (PioG) injection offset the pro-tumorigenic effect of chronic stress. Moreover, specific β₂-adrenergic receptor (β₂R) antagonist ICI11-8551 inhibited the effect of chronic stress. <i>In vitro</i>, norepinephrine (NE) treatment had a similar tendency to chronic stress. The effect of NE was mediated by the β₂R/adenylate cyclase signaling pathway and suppressed by PioG. PPARγ suppressed VEGF/FGF2 through reactive oxygen species inhibition. Bioinformatics data confirmed that therewas a lowPPARγ expression in breast invasive carcinoma. Lower PPARγ was associated with a significantly worse survival.Conclusion β₂R activation induced by chronic stress and related hormones promotes growth and VEGF/FGF2-mediated angiogenesis of breast cancer by down-regulating PPARγ. Our findings hint that β receptor and PPARγ as two target molecules and the novel role for their agonists or antagonists as clinical medicine in breast cancer therapy

Prior studies have noted that Zinc nger E-box binding homeobox 1 (ZEB1) is a master transcription regulator, affecting the expression of nearly 2,000 genes in breast cancer cells, especially in epithelial-mesenchymal transition (EMT) process. In this study, we found that ZEB1 directly regulated Glutathione peroxidase 4 (GPX4) transcriptions, which was closely related to tumor reactive oxygen species (ROS) metabolism. We selected two human breast cancer cell linesMDA-MB-231 and MCF7 for ROS test, PCR, immuno uorescence, western blot, ChIP, luciferase assay and enzyme assay. The conclusions continue to be supported in mouse models and bioinformatics analysis. We found that ZEB1 directly bound to GPX4 promoter E-box motif (CANNTG) to inhibit GPX4 transcription, which contributing to ROS accumulation and tumorigenesis in breast cancer.

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Triple-negative breast cancer (TNBC) has the highest percentage of lymphocytic infiltration among breast cancer subtypes, and TNBC patients may benefit from anti-PD-1/PD-L1 immunotherapy. However, some cases whether the immune checkpoint blockade (ICB) shows low targeting efficiency have occurred and effective synergistic targets need to be found, which inspired our exploration of the co-expression analysis of MCT4 (SLC16A3) and PD-L1 (CD274) and their potential regulatory mechanisms. After bioinformatic analysis of the relationship between MCT4 and PD-L1, we validated their positive co-expression relationship in triple-negative breast cancer through multiple immunohistochemical staining (mIHC), CRISPR/Cas9, and lentiviral transduction for MCT4 knockout (sgMCT4/231 KO) or overexpression (pEGFP-N1-MCT4/231). We examined the effect of lactate treatment on PD-L1 expression in triple-negative breast cancer cells by qRT-PCR and Western blot. Combined with our results, we found that MCT4 positively regulated PD-L1 expression through discharging lactate and stabilized PD-L1 through promoting its glycosylation by the classic WNT pathway in MDA-MB-231 cells. More importantly, the high co-expression of MCT4 and PD-L1 appears to predict more effective targets for treating TNBC, which would improve immune checkpoint therapy for TNBC.