The targetable nanoparticle BAF312@cRGD-CaP-NP represses tumor growth and angiogenesis by downregulating the S1PR1/P-STAT3/VEGFA axis in triple-negative breast cancer

Gong, Ke; Jiao, Juyang; Xu, Chaoqun; Dong, Yang; Li, Dongxiao; He, Dongyang; Zhao, Dekuang; Yu, Jian; Sun, Ying; Zhang, Wei; Bai, Mingwen; Duan, Yourong

doi:10.1186/s12951-021-00904-6

Cited by 14 publications

(9 citation statements)

References 51 publications

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“…Given the recent findings that S1P1 is important for TNBC survival [ 22 , 23 ], we next performed a Western blot analysis to assess the protein levels of S1P1 in a panel of human TNBC and less aggressive luminal breast cancer cell lines, as well as a nontransformed breast epithelial cell line (MCF10A) ( Figure 1 d). Consistent with our transcript findings, we did not detect significant differences in total S1P1 protein levels between TNBC and luminal breast cancer cells ( Figure 1 e).…”

Section: Resultsmentioning

confidence: 99%

“…In the context of breast cancer, high S1P1 levels correlate with rapid recurrence rates, shorter survival times, and increased resistance to tamoxifen in ER-positive breast cancer patients [ 21 ]. Emerging evidence revealed that several experimental treatments can kill TNBC by downregulating S1P1 signaling, suggesting its importance in TNBC survival [ 22 , 23 ]. Hence, it is crucial to apply animal models to gain an in-depth understanding of this receptor in TNBC pathogenesis to guide therapeutic selection.…”

Section: Introductionmentioning

confidence: 99%

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S1P1 Threonine 236 Phosphorylation Mediates the Invasiveness of Triple-Negative Breast Cancer and Sensitivity to FTY720

Laroche

Shen

et al. 2023

Cells

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Hyperactive sphingosine 1-phosphate (S1P) signaling is associated with a poor prognosis of triple-negative breast cancer (TNBC). Despite recent evidence that links the S1P receptor 1 (S1P1) to TNBC cell survival, its role in TNBC invasion and the underlying mechanisms remain elusive. Combining analyses of human TNBC cells with zebrafish xenografts, we found that phosphorylation of S1P receptor 1 (S1P1) at threonine 236 (T236) is critical for TNBC dissemination. Compared to luminal breast cancer cells, TNBC cells exhibit a significant increase of phospho-S1P1 T236 but not the total S1P1 levels. Misexpression of phosphorylation-defective S1P1 T236A (alanine) decreases TNBC cell migration in vitro and disease invasion in zebrafish xenografts. Pharmacologic disruption of S1P1 T236 phosphorylation, using either a pan-AKT inhibitor (MK2206) or an S1P1 functional antagonist (FTY720, an FDA-approved drug for treating multiple sclerosis), suppresses TNBC cell migration in vitro and tumor invasion in vivo. Finally, we show that human TNBC cells with AKT activation and elevated phospho-S1P1 T236 are sensitive to FTY720-induced cytotoxic effects. These findings indicate that the AKT-enhanced phosphorylation of S1P1 T236 mediates much of the TNBC invasiveness, providing a potential biomarker to select TNBC patients for the clinical application of FTY720.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

S1P1 Threonine 236 Phosphorylation Mediates the Invasiveness of Triple-Negative Breast Cancer and Sensitivity to FTY720

Laroche

Shen

et al. 2023

Cells

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“…The CD8 and CD4 T cells are the key components of the cancer microenvironment, which is strongly related to the occurrence and development of cancer [ 34 , 35 ]. An increasing number of studies has found that not only the immune cells but also the stromal cells play important roles in the progression and prognosis of tumors [ 36 , 37 , 38 , 39 ]. For example, the osteoblasts, the first bone-resident cells identified to regulate hematopoiesis, were posited as the remote regulators of lung cancer [ 40 ].…”

Section: Resultsmentioning

confidence: 99%

Tumor Microenvironment Characterization in Breast Cancer Identifies Prognostic Pathway Signatures

Qiu

Han

et al. 2022

Genes

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Breast cancer is one of the most common female malignancies worldwide. Due to its early metastases formation and a high degree of malignancy, the 10 year-survival rate of metastatic breast cancer does not exceed 30%. Thus, more precise biomarkers are urgently needed. In our study, we first estimated the tumor microenvironment (TME) infiltration using the xCell algorithm. Based on TME infiltration, the three main TME clusters were identified using consensus clustering. Our results showed that the three main TME clusters cause significant differences in survival rates and TME infiltration patterns (log-rank test, p = 0.006). Then, multiple machine learning algorithms were used to develop a nine-pathway-based TME-related risk model to predict the prognosis of breast cancer (BRCA) patients (the immune-related pathway-based risk score, defined as IPRS). Based on the IPRS, BRCA patients were divided into two subgroups, and patients in the IPRS-low group presented significantly better overall survival (OS) rates than the IPRS-high group (log-rank test, p < 0.0001). Correlation analysis revealed that the IPRS-low group was characterized by increases in immune-related scores (cytolytic activity (CYT), major histocompatibility complex (MHC), T cell-inflamed immune gene expression profile (GEP), ESTIMATE, immune, and stromal scores) while exhibiting decreases in tumor purity, suggesting IPRS-low patients may have a strong immune response. Additionally, the gene-set enrichment analysis (GSEA) result confirmed that the IPRS-low patients were significantly enriched in several immune-associated signaling pathways. Furthermore, multivariate Cox analysis revealed that the IPRS was an independent prognostic biomarker after adjustment by clinicopathologic characteristics. The prognostic value of the IPRS model was further validated in three external validation cohorts. Altogether, our findings demonstrated that the IPRS was a powerful predictor to screen out certain populations with better prognosis in breast cancer and may serve as a potential biomarker guiding clinical treatment decisions.

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“…Moreover, the radical-containing nanoparticles increased the anti-angiogenic activity in breast cancer [ 112 ]. In the study of Gong et al [ 113 ], nanoparticles delivering a sphingosine-1 phosphate receptor inhibitor drastically inhibited triple negative breast cancer growth and angiogenesis in vivo. Summary of the described data is included in Table 2 .…”

Section: Possible Utility Of the Vegf Family Members In Breast Cancermentioning

confidence: 99%

Vascular Endothelial Growth Factor Ligands and Receptors in Breast Cancer

Brogowska

Zajkowska

Mroczko

2023

JCM

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Breast cancer (BC) is the most common malignancy responsible for the largest number of deaths in women worldwide. The risk of developing BC is predisposed by many factors such as age, presence of genetic mutations or body weight. The diagnosis is mostly made relatively late, which is why patients are exposed to radical surgical treatments, long-term chemotherapy and lower survival rates. There are no sufficiently sensitive and specific screening tests; therefore, researchers are still looking for new diagnostic biomarkers that would indicate the appearance of neoplastic changes in the initial stage of neoplasm. The VEGF family of proteins (VEGF-A, VEGF-B, VEGF-C, VEGF-D, EG-VEGF, PlGF) and their receptors are significant factors in the pathogenesis of BC. They play a significant role in the process of angiogenesis and lymphangiogenesis in both physiological and pathological conditions. The usefulness of these proteins as potential diagnostic biomarkers has been initially proven. Moreover, the blockage of VEGF-related pathways seems to be a valid therapeutic target. Recent studies have tried to describe novel strategies, including targeting pericytes, use of miRNAs and extracellular tumor-associated vesicles, immunotherapeutic drugs and nanotechnology. This indicates their possible contribution to the formation of breast cancer and their usefulness as potential biomarkers and therapeutic targets.

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The targetable nanoparticle BAF312@cRGD-CaP-NP represses tumor growth and angiogenesis by downregulating the S1PR1/P-STAT3/VEGFA axis in triple-negative breast cancer

Cited by 14 publications

References 51 publications

S1P1 Threonine 236 Phosphorylation Mediates the Invasiveness of Triple-Negative Breast Cancer and Sensitivity to FTY720

S1P1 Threonine 236 Phosphorylation Mediates the Invasiveness of Triple-Negative Breast Cancer and Sensitivity to FTY720

Tumor Microenvironment Characterization in Breast Cancer Identifies Prognostic Pathway Signatures

Vascular Endothelial Growth Factor Ligands and Receptors in Breast Cancer

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