Jie Liu

Breast cancer stem cells are recognized as the key factors contributing to breast cancer progression and drug resistance, while polarity proteins play a pivotal role in regulating the fate of cancer stem cells and the progression of malignant tumors. However, the function of the polarity protein MALS3 in modulating cancer stem cell-like properties remains unclear. Here, we identify that the loss of the polarity protein MALS3 disrupts the homeostasis of mammary epithelial cells while increasing breast cancer stem cell-like properties. Mechanistically, MALS3 utilizes its L27 domain to mediate the interaction between the kinase LATS1 and TAZ, thereby promoting the phosphorylation of TAZ. Furthermore, MALS3 can recruit the E3 ubiquitin ligase TRIM29 to interact with TAZ. Subsequently, TRIM29 ultimately drives the degradation of TAZ via K48-linked polyubiquitination, and this regulatory process operates independently of the classical Hippo signaling pathway. We discover that the MALS3 upregulator mirtazapine suppresses stem cell-like properties and effectively enhances tumor sensitivity to doxorubicin in vivo. This study reveals the molecular mechanism by which the polarity protein MALS3 regulates breast cancer stem cell-like properties and suggests that MALS3 upregulation via mirtazapine may enhance tumor sensitivity to chemotherapeutic drugs.

Tumor-derived exosomes bind to organ resident cells, activating S100 molecules during the remodeling of the local immune microenvironment. However, little is known regarding how organ resident cell S100A10 mediates cancer metastatic progression. Here, we provided evidence that S100A10 plays an important role in regulating the lung immune microenvironment and cancer metastasis. S100A10-deficient mice reduced cancer metastasis in the lung. Furthermore, the activation of S100A10 within lung fibroblasts via tumor-derived exosomes increased the expression of CXCL1 and CXCL8 chemokines, accompanied by the myeloid-derived suppressor cells (MDSCs) recruitment. S100A10 inhibitors such as 1-Substituted-4-Aroyl-3-hydroxy-5-Phenyl-1 H-5-pyrrol-2(5 H)-ones inhibit lung metastasis in vivo. Our findings highlight the crucial role of S100A10 in driving MDSC recruitment in order to remodel the lung immune microenvironment and provide potential therapeutic targets to block cancer metastasis to the lung.

Background: As a highly prevalent malignancy among women worldwide, breast cancer, remains a critical public health issue necessitating the development of novel therapeutics and biomarkers. Kruppel Like Factor 2 (KLF2), a member of the Kruppel family of transcription factors, has been implicated in various types of cancer due to its diminished expression; however, the potential implications of KLF2 expression in relation to breast cancer progression, prognosis, and therapy remain unclear.Methods: The present study employed the Tumor Immune Estimation Resource (TIMER) and The Human Protein Atlas databases to investigate the expression pattern of KLF2 in pan-cancer. The relationship between KLF2 expression and clinical features or immune infiltration of The Cancer Genome Atlas (TCGA) breast cancer samples was evaluated using Breast Cancer Integrative Platform (BCIP) and TIMER. The expression levels of KLF2 in breast cancer were validated via immunohistochemical staining analysis. Gene Set Enrichment Analysis (GSEA) to study the KLF2-related gene ontology. STRING database was employed to construct a protein-protein interaction (PPI) network of KLF2 in relation to vascular endothelial growth factor A (VEGFA) and hypoxia-inducible factor 1α (HIF1α). The expression of KLF2 following diverse breast cancer therapies was analyzed in the Gene Expression Omnibus (GEO) databases. The expression of KLF2 following treatment with simvastatin was validated via immunofluorescence and western blotting.Results: Our study reveals that KLF2 displays significantly reduced expression in cancerous tissues compared to non-cancerous controls. Patients with low KLF2 expression levels exhibited poor prognosis across multiple cancer types. KLF2 expression levels were found to be reduced in advanced cancer stages and grades, while positively correlated with the expression of estrogen receptor (ER), progesterone receptor (PR), and tumor size in breast cancer. KLF2 expression is associated with diverse immune infiltration cells, and may impact the breast tumor immune microenvironment by regulating dendritic cell activation. Additionally, we observed a negative correlation between KLF2 expression levels and angiogenesis, as well as the expression of VEGFA and HIF1α. Notably, the anticancer drug simvastatin could induce KLF2 expression in both breast cancer.Conclusion: Based on our observations, KLF2 has potential as a diagnostic, prognostic, and therapeutic biomarker for breast cancer.