High Expression of CEMIP Correlates Poor Prognosis and the Tumur Microenvironment in Breast Cancer as a Promisingly Prognostic Biomarker

Cell migration-inducing hyaluronidase 1 (CEMIP), a Wnt-related protein and also known as KIAA1199, is implicated in the process of metastatic colonization in a variety of malignant tumors, including breast cancer (BC), which is one of the most frequently diagnosed tumors in women worldwide. In this study, multiple public databases, online analytical tools, and bioinformatics approaches were applied to explore the expression levels, regulatory mechanisms, and biological functions of CEMIP in BC. We illustrated that CEMIP was highly expressed in various kinds of carcinomas, including BC, especially advanced subtypes, and predicted less favorable prognosis (negatively associated with overall survival) in BC patients, which might be an independent prognostic factor. Then, we revealed that the mutation and high expression of CEMIP might lead to it as an oncogene. We also demonstrated that TP53 mutation, DNA hypo-methylation, and the expression changes of three potential upstream transcription factors (EZH2, EGR1, and JUN) of CEMIP were likely to cause the hyperexpression of CEMIP in BC. Moreover, our findings suggested that CEMIP might exert its carcinogenic roles in the tumor microenvironment via participation in the extracellular matrix formation, increasing cancer-associated fibroblast (CAF), M2 macrophage, and neutrophil infiltration and decreasing CD8+ T cell infiltration. In summary, our study provided more solid evidence for CEMIP as a prognostic and metastatic biomarker and a potential therapeutic target in BC. Of course, these findings also need more confirmations of basic experiments and further clinical trials in the future.

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MiRNA10b-directed nanotherapy effectively targets brain metastases from breast cancer

Scientific Reports ◽

10.1038/s41598-021-82528-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Byunghee Yoo ◽

Alana Ross ◽

Pamela Pantazopoulos ◽

Zdravka Medarova

Keyword(s):

Breast Cancer ◽

Rna Interference ◽

Lymph Nodes ◽

Therapeutic Effect ◽

Metastatic Breast ◽

Treatment Modalities ◽

Transcriptional Level ◽

Metastatic Progression ◽

Therapeutic Modalities ◽

Metastatic Colonization

AbstractRNA interference represents one of the most appealing therapeutic modalities for cancer because of its potency, versatility, and modularity. Because the mechanism is catalytic and affects the expression of disease-causing antigens at the post-transcriptional level, only small amounts of therapeutic need to be delivered to the target in order to exert a robust therapeutic effect. RNA interference is also advantageous over other treatment modalities, such as monoclonal antibodies or small molecules, because it has a much broader array of druggable targets. Finally, the complementarity of the genetic code gives us the opportunity to design RNAi therapeutics using computational, rational approaches. Previously, we developed and tested an RNAi-targeted therapeutic, termed MN-anti-miR10b, which was designed to inhibit the critical driver of metastasis and metastatic colonization, miRNA-10b. We showed in animal models of metastatic breast cancer that MN-anti-miR10b accumulated into tumors and metastases in the lymph nodes, lungs, and bone, following simple intravenous injection. We also found that treatment incorporating MN-anti-miR10b was effective at inhibiting the emergence of metastases and could regress already established metastases in the lymph nodes, lungs, and bone. In the present study, we extend the application of MN-anti-miR10b to a model of breast cancer metastatic to the brain. We demonstrate delivery to the metastatic lesions and obtain evidence of a therapeutic effect manifested as inhibition of metastatic progression. This investigation represents an additional step towards translating similar RNAi-targeted therapeutics for the systemic treatment of metastatic disease.

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Pilose antler polypeptides promote chemosensitization and T-cell infiltration of triple-negative breast cancer

Journal of Functional Foods ◽

10.1016/j.jff.2021.104664 ◽

2021 ◽

Vol 85 ◽

pp. 104664

Author(s):

Mohan Li ◽

Kexin Zheng ◽

Shiliang Ma ◽

Pengpeng Hu ◽

Bo Yuan ◽

...

Keyword(s):

Breast Cancer ◽

T Cell ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Cell Infiltration ◽

T Cell Infiltration

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VWCE as a potential biomarker associated with immune infiltrates in breast cancer

Cancer Cell International ◽

10.1186/s12935-021-01955-3 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Qin Huo ◽

Zhenwei Li ◽

Siqi Chen ◽

Juan Wang ◽

Jiaying Li ◽

...

Keyword(s):

Breast Cancer ◽

Immune Cell ◽

Her2 Status ◽

Cancer Tissue ◽

M2 Macrophage ◽

Breast Cancer Patients ◽

Immune Infiltration ◽

Potential Biomarker ◽

Significant Difference ◽

Factor C

Abstract Purpose Von Willebrand Factor C and EGF Domains (VWCE) is an important gene that regulates cell adhesion, migration, and interaction. However, the correlation between VWCE expression and immune infiltrating in breast cancer remain unclear. In this study, we investigated the correlation between VWCE expression and immune infiltration levels in breast cancer. Methods The expression of VWCE was analyzed by the tumor immune estimation resource (TIMER) and DriverDB databases. Furthermore, genes co-expressed with VWCE and gene ontology (GO) enrichment analysis were investigated by the STRING and Enrichr web servers. Also, we performed the single nucleotide variation (SNV), copy number variation (CNV), and pathway activity analysis through GSCALite. Subsequently, the relationship between VWCE expression and tumor immunity was analyzed by TIMER and TISIDB databases, and further verified the results using Quantitative Real-Time PCR (RT-PCR), Western blotting, and immunohistochemistry. Results The results showed that the expression of VWCE mRNA in breast cancer tissue was significantly lower than that in normal tissues. We found that the expression level of VWCE was associated with subtypes, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status of breast cancer patients, but there was no significant difference in the expression of VWCE was found in age and nodal status. Further analyses indicated that VWCE was correlated with the activation or inhibition of multiple oncogenic pathways. Additionally, VWCE expression was negatively correlated with the expression of STAT1 (Th1 marker, r = − 0.12, p = 6e−05), but positively correlated with the expression of MS4A4A (r = 0.28, p = 0). These results suggested that the expression of VWCE was correlated with immune infiltration levels of Th1 and M2 macrophage in breast cancer. Conclusions In our study, VWCE expression was associated with a better prognosis and was immune infiltration in breast cancer. These findings demonstrate that VWCE is a potential prognostic biomarker and correlated with tumor immune cell infiltration, and maybe a promising therapeutic target in breast cancer.

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Ivermectin converts cold tumors hot and synergizes with immune checkpoint blockade for treatment of breast cancer

npj Breast Cancer ◽

10.1038/s41523-021-00229-5 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Dobrin Draganov ◽

Zhen Han ◽

Aamir Rana ◽

Nitasha Bennett ◽

Darrell J. Irvine ◽

...

Keyword(s):

Breast Cancer ◽

Immune Responses ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Synergistic Activity ◽

Primary Tumors ◽

T Cell Infiltration ◽

Cancer Cell Death ◽

Bona Fide

AbstractWe show that treatment with the FDA-approved anti-parasitic drug ivermectin induces immunogenic cancer cell death (ICD) and robust T cell infiltration into breast tumors. As an allosteric modulator of the ATP/P2X4/P2X7 axis which operates in both cancer and immune cells, ivermectin also selectively targets immunosuppressive populations including myeloid cells and Tregs, resulting in enhanced Teff/Tregs ratio. While neither agent alone showed efficacy in vivo, combination therapy with ivermectin and checkpoint inhibitor anti-PD1 antibody achieved synergy in limiting tumor growth (p = 0.03) and promoted complete responses (p < 0.01), also leading to immunity against contralateral re-challenge with demonstrated anti-tumor immune responses. Going beyond primary tumors, this combination achieved significant reduction in relapse after neoadjuvant (p = 0.03) and adjuvant treatment (p < 0.001), and potential cures in metastatic disease (p < 0.001). Statistical modeling confirmed bona fide synergistic activity in both the adjuvant (p = 0.007) and metastatic settings (p < 0.001). Ivermectin has dual immunomodulatory and ICD-inducing effects in breast cancer, converting cold tumors hot, thus represents a rational mechanistic partner with checkpoint blockade.

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High expression levels of egfl7 correlate with low endothelial cell activation in peritumoral vessels of human breast cancer

Oncology Letters ◽

10.3892/ol.2016.4791 ◽

2016 ◽

Vol 12 (2) ◽

pp. 1422-1428 ◽

Cited By ~ 7

Author(s):

Diane Pannier ◽

Géraldine Philippin-Lauridant ◽

Marie-Christine Baranzelli ◽

Delphine Bertin ◽

Emilie Bogart ◽

...

Keyword(s):

Breast Cancer ◽

Endothelial Cell ◽

Human Breast Cancer ◽

Cell Activation ◽

High Expression ◽

Human Breast ◽

Endothelial Cell Activation ◽

Expression Levels ◽

Peritumoral Vessels

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Effects of Steady Low-Intensity Exercise on High-Fat Diet Stimulated Breast Cancer Progression Via the Alteration of Macrophage Polarization

Integrative Cancer Therapies ◽

10.1177/1534735420949678 ◽

2020 ◽

Vol 19 ◽

pp. 153473542094967

Author(s):

Min Kyoon Kim ◽

Yesl Kim ◽

SeungHwa Park ◽

Eunju Kim ◽

Yerin Kim ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Growth ◽

High Fat Diet ◽

Tumor Volume ◽

Macrophage Polarization ◽

M2 Macrophage ◽

High Fat ◽

Low Intensity ◽

M2 Macrophage Polarization ◽

Low Intensity Exercise

Physical inactivity and high-fat diet, especially high saturated fat containing diet are established risk factors for breast cancer that are amenable to intervention. High-fat diet has been shown to induce tumor growth and metastasis by alteration of inflammation but steady exercise has anti-tumorigenic effects. However, the mechanisms underlying the effects of physical activity on high-fat diet stimulated breast cancer initiation and progression are currently unclear. In this study, we examined how the intensity of physical activity influences high fat diet-stimulated breast cancer latency and progression outcomes, and the possible mechanisms behind these effects. Five-week-old female Balb/c mice were fed either a control diet or a high-fat diet for 8 weeks, and then 4T1 mouse mammary tumor cells were inoculated into the mammary fat pads. Exercise training occurred before tumor cell injection, and tumor latency and tumor volume were measured. Mice with a high-fat diet and low-intensity exercise (HFLE) had a longer tumor latency period, slower tumor growth, and smaller tumor volume in the final tumor assessment compared with the control, high-fat diet control (HFDC), and high-fat diet with moderate-intensity exercise (HFME) groups. Steady low- and moderate-intensity exercise had no effect on cell proliferation but induced apoptosis by activating caspase-3 through the alteration of Bcl-2, Bcl-xL, and Bax expression. Furthermore, steady exercise reduced M2 macrophage polarization in breast tumor tissue, which has been linked to tumor growth. The myokine, myostatin, reduced M2 macrophage polarization through the inhibition of the JAK-STAT signaling pathway. These results suggest that steady low-intensity exercise could delay breast cancer initiation and growth and reduce tumor volume through the induction of tumor cell apoptosis and the suppression of M2 macrophage polarization.

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Role of the NUDT Enzymes in Breast Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms22052267 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2267

Author(s):

Roni H. G. Wright ◽

Miguel Beato

Keyword(s):

Breast Cancer ◽

Signaling Pathways ◽

Cancer Progression ◽

Breast Cancers ◽

Metastatic Colonization ◽

Hormone Receptor Positive ◽

Aggressive Cancer ◽

Cancer Types ◽

Metastatic Process

Despite global research efforts, breast cancer remains the leading cause of cancer death in women worldwide. The majority of these deaths are due to metastasis occurring years after the initial treatment of the primary tumor and occurs at a higher frequency in hormone receptor-positive (Estrogen and Progesterone; HR+) breast cancers. We have previously described the role of NUDT5 (Nudix-linked to moiety X-5) in HR+ breast cancer progression, specifically with regards to the growth of breast cancer stem cells (BCSCs). BCSCs are known to be the initiators of epithelial-to-mesenchyme transition (EMT), metastatic colonization, and growth. Therefore, a greater understanding of the proteins and signaling pathways involved in the metastatic process may open the door for therapeutic opportunities. In this review, we discuss the role of NUDT5 and other members of the NUDT family of enzymes in breast and other cancer types. We highlight the use of global omics data based on our recent phosphoproteomic analysis of progestin signaling pathways in breast cancer cells and how this experimental approach provides insight into novel crosstalk mechanisms for stratification and drug discovery projects aiming to treat patients with aggressive cancer.

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