scholarly journals Desensitization of Capsaicin-Sensitive Afferents Accelerates Early Tumor Growth via Increased Vascular Leakage in a Murine Model of Triple Negative Breast Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Noémi Bencze ◽  
Csaba Schvarcz ◽  
Gábor Kriszta ◽  
Lea Danics ◽  
Éva Szőke ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Enzyme Activity ◽  
Tumor Growth ◽  
Triple Negative ◽  
Vascular Leakage ◽  
Size Difference ◽  
Control Group ◽  
Protease Enzyme

There is growing interest in the role of nerve-driven mechanisms in tumorigenesis and tumor growth. Capsaicin-sensitive afferents have been previously shown to possess antitumoral and immune-regulatory properties, the mechanism of which is currently poorly understood. In this study, we have assessed the role of these terminals in the triple negative 4T1 orthotopic mouse model of breast cancer. The ultrapotent capsaicin-analogue resiniferatoxin (RTX) was used for the selective, systemic desensitization of capsaicin-sensitive afferents. Growth and viability of orthotopically implanted 4T1 tumors were measured by caliper, in vivo MRI, and bioluminescence imaging, while tumor vascularity and protease enzyme activity were assessed using fluorescent in vivo imaging. The levels of the neuropeptides Calcitonin Gene-Related Peptide (CGRP), Substance P (SP), and somatostatin were measured from tumor tissue homogenates using radioimmunoassay, while tumor structure and peritumoral inflammation were evaluated by conventional use of CD31, CD45 and CD3 immunohistology. RTX-pretreated mice demonstrated facilitated tumor growth in the early phase measured using a caliper, which was coupled with increased tumor vascular leakage demonstrated using fluorescent vascular imaging. The tumor size difference dissipated by day seven. The MRI tumor volume was similar, while the intratumoral protease enzyme activity measured by fluorescence imaging was also comparable in RTX-pretreated and non-pretreated animals. Tumor viability or immunohistopathological profile was measured using CD3, CD31, and CD45 stains and did not differ significantly from the non-pretreated control group. Intratumoral somatostatin, CGRP, and SP levels were similar in both groups. Our results underscore the beneficial, antitumoral properties of capsaicin sensitive nerve terminals in this aggressive model of breast cancer, which is presumed to be due to the inhibition of tumor vascular bed disruption. The absence of any difference in intratumoral neuropeptide levels indicates non-neural sources playing a substantial part in their expression.

scholarly journals Edelfosine nanoemulsions inhibit tumor growth of triple negative breast cancer in zebrafish xenograft model

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sofia M. Saraiva ◽  
Carlha Gutiérrez-Lovera ◽  
Jeannette Martínez-Val ◽  
Sainza Lores ◽  
Belén L. Bouzo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Xenograft Model ◽  
Skin Barrier ◽  
Zebrafish Embryos ◽  
Biorelevant Media

AbstractTriple negative breast cancer (TNBC) is known for being very aggressive, heterogeneous and highly metastatic. The standard of care treatment is still chemotherapy, with adjacent toxicity and low efficacy, highlighting the need for alternative and more effective therapeutic strategies. Edelfosine, an alkyl-lysophospholipid, has proved to be a promising therapy for several cancer types, upon delivery in lipid nanoparticles. Therefore, the objective of this work was to explore the potential of edelfosine for the treatment of TNBC. Edelfosine nanoemulsions (ET-NEs) composed by edelfosine, Miglyol 812 and phosphatidylcholine as excipients, due to their good safety profile, presented an average size of about 120 nm and a neutral zeta potential, and were stable in biorelevant media. The ability of ET-NEs to interrupt tumor growth in TNBC was demonstrated both in vitro, using a highly aggressive and invasive TNBC cell line, and in vivo, using zebrafish embryos. Importantly, ET-NEs were able to penetrate through the skin barrier of MDA-MB 231 xenografted zebrafish embryos, into the yolk sac, leading to an effective decrease of highly aggressive and invasive tumoral cells’ proliferation. Altogether the results demonstrate the potential of ET-NEs for the development of new therapeutic approaches for TNBC.

scholarly journals Antiproliferative Effect of Androgen Receptor Inhibition in Mesenchymal Stem-Like Triple-Negative Breast Cancer

2016 ◽  
Vol 38 (3) ◽  
pp. 1003-1014 ◽  
Author(s):  
Aiyu Zhu ◽  
Yan Li ◽  
Wei Song ◽  
Yumei Xu ◽  
Fang Yang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Androgen Receptor ◽  
Cyclin D1 ◽  
Cancer Cells ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cells ◽  
Triple Negative

Background/Aims: Androgen receptor (AR), a steroid hormone receptor, has recently emerged as prognostic and treatment-predictive marker in breast cancer. Previous studies have shown that AR is widely expressed in up to one-third of triple-negative breast cancer (TNBC). However, the role of AR in TNBC is still not fully understood, especially in mesenchymal stem-like (MSL) TNBC cells. Methods: MSL TNBC MDA-MB-231 and Hs578T breast cancer cells were exposed to various concentration of agonist 5-α-dihydrotestosterone (DHT) or nonsteroidal antagonist bicalutamide or untreated. The effects of AR on cell viability and apoptosis were determined by MTT assay, cell counting, flow cytometry analysis and protein expression of p53, p73, p21 and Cyclin D1 were analyzed by western blotting. The bindings of AR to p73 and p21 promoter were detected by ChIP assay. MDA-MB-231 cells were transplanted into nude mice and the tumor growth curves were determined and expression of AR, p73 and p21 were detected by Immunohistochemistry (IHC) staining after treatment of DHT or bicalutamide. Results: We demonstrate that AR agonist DHT induces MSL TNBC breast cancer cells proliferation and inhibits apoptosis in vitro. Similarly, activated AR significantly increases viability of MDA-MB-231 xenografts in vivo. On the contrary, AR antagonist, bicalutamide, causes apoptosis and exerts inhibitory effects on the growth of breast cancer. Moreover, DHT-dependent activation of AR involves regulation in the cell cycle related genes, including p73, p21 and Cyclin D1. Further investigations indicate the modulation of AR on p73 and p21 mediated by direct binding of AR to their promoters, and DHT could make these binding more effectively. Conclusions: Our study demonstrates the tumorigenesis role of AR and the inhibitory effect of bicalutamide in AR-positive MSL TNBC both in vitro and in vivo, suggesting that AR inhibition could be a potential therapeutic approach for AR-positive TNBC patients.

scholarly journals Interfering MSN-NONO complex–activated CREB signaling serves as a therapeutic strategy for triple-negative breast cancer

2020 ◽  
Vol 6 (8) ◽  
pp. eaaw9960 ◽  
Author(s):  
Yuanyuan Qin ◽  
Weilong Chen ◽  
Guojuan Jiang ◽  
Lei Zhou ◽  
Xiaoli Yang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Cancer Cell Proliferation ◽  
Poor Overall Survival ◽  
Kinase C ◽  
Life Threatening

Triple-negative breast cancer (TNBC) is life-threatening because of limited therapies and lack of effective therapeutic targets. Here, we found that moesin (MSN) was significantly overexpressed in TNBC compared with other subtypes of breast cancer and was positively correlated with poor overall survival. However, little is known about the regulatory mechanisms of MSN in TNBC. We found that MSN significantly stimulated breast cancer cell proliferation and invasion in vitro and tumor growth in vivo, requiring the phosphorylation of MSN and a nucleoprotein NONO-assisted nuclear localization of phosphorylated MSN with protein kinase C (PKC) and then the phosphorylation activation of CREB signaling by PKC. Our study also demonstrated that targeting MSN, NONO, or CREB significantly inhibited breast tumor growth in vivo. These results introduce a new understanding of MSN function in breast cancer and provide favorable evidence that MSN or its downstream molecules might serve as new targets for TNBC treatment.

Effective treatment of triple-negative breast cancer with targeted cytotoxic somatostatin analogue AN-162 (AEZS-124)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 619-619
Author(s):  
S. Seitz ◽  
A. V. Schally ◽  
S. Gluck ◽  
F. Rick ◽  
L. Szalontay ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Fluorescence Microscopy ◽  
Tumor Growth ◽  
Cell Line ◽  
Triple Negative ◽  
Somatostatin Analogue ◽  
Tnbc Cell ◽  
Tnbc Cell Line ◽  
Fluorescence Assays

619 Background: Triple negative breast cancers (TNBC) represent a distinct subtype of breast cancer being negative to ER, PR and HER2 and are associated with poor prognosis. Limited systemic treatment options exist for TNBC. TNBC cells express somatostatin receptors (SSTR). Therefore, to investigate preclinical characteristics of TNBC we used a novel targeted cytotoxic somatostatin analogue AN-162 containing doxorubicin (DOX) which binds to the subtypes 2, 3 and 5 of SSTR. Methods: The expression of SSTR in HCC 1806 human TNBC cell line was detected by RT-PCR. Cytotoxic effect of AN-162 in vitro was visualized by ethidium bromide staining fluorescence microscopy. Internalization of AN-162 into HCC 1806 cells was tested by 125Iodide-labeled AN-162 uptake assays and the presence of DOX in the nucleus was measured by fluorescence assays after separating the nucleus from the cytoplasm. For in vivo experiments, HCC 1806 TNBC cells were xenografted subcutaneously into nude mice which were then randomized into four groups receiving AN-162, DOX, an unconjugated mixture of DOX and somatostatin analogue RC-160 at the same equimolar dose of 2.5 μmol/kg (1.45 mg/kg Dox equivalent) i.v. (q7d 4x) and vehicle solution control. Results: HCC 1806 TNBC cell line was positive for the expression of all five SSTR receptor subtypes. Ethidum bromide staining of cells treated with 2.5 μM of AN-162 for 30 min demonstrated cell death after 24h by fluorescence microscopy. Uptake assays with AN-162 showed specific internalization of AN-162 into the cells mediated through the sstrs. After treatment of the cells with 2.5 μM AN-162 for 10 or 30 min, DOX could be detected in the nucleus by fluorescence assays. In vivo, AN-162 significantly (p<0.05) inhibited tumor growth of HCC 1806 xenografts compared to Control, DOX and the unconjugated mixture of DOX+RC-160 from day 14 and the inhibition remained significant until the end of the study on day 35. Conclusions: Our results indicate that treatment with targeted cytotoxic somatostatin analogue AN-162 produces a greater inhibition of tumor growth than DOX alone in somatostatin receptor positive TNBC. Our findings support the concept of targeted chemotherapy based on cytotoxic peptide analogues for the treatment of breast cancer and other cancers. No significant financial relationships to disclose.

Paradoxical Hormone Responses of KPL-1 Breast Cancer Cells in vivo: A Significant Role of Angiogenesis in Tumor Growth

Oncology ◽  
2000 ◽  
Vol 59 (2) ◽  
pp. 158-165 ◽  
Author(s):  
Junichi Kurebayashi ◽  
Hironori Kunisue ◽  
Shigeru Yamamoto ◽  
Masafumi Kurosumi ◽  
Takemi Otsuki ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Significant Role ◽  
Breast Cancer Cells ◽  
Hormone Responses

scholarly journals Human Drug Efflux Transporter ABCC5 Confers Sensitivity and Acquired Resistance to Pemetrexed in Breast Cancer

2020 ◽  
Author(s):  
Jihui Chen ◽  
Zhipeng Wang ◽  
Shouhong Gao ◽  
Kejin Wu ◽  
Fang Bai ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Abc Transporters ◽  
Cancer Cell Lines ◽  
Control Group ◽  
Over Expression ◽  
Mcf 7

Abstract AimPemetrexed, a new generation antifolate drug, is approved for the treatment for locally advanced or metastatic breast cancer, but factors affecting the efficacy and resistance of it have yet to be fully explicit. ATP-binding cassette transporters have been reported as prognostic and adverse effects predictors of many xenobiotics. This study was designed to explore whether ABC transporters affect pemetrexed resistance and may contribute to treatment regimen optimization for breast cancer.MethodsFirstly, the expression of ABC transporters family members was measured in cell lines, thereafter examined the potential role of ABC transporter in conferring resistance to pemetrexed in primary cancer cell lines isolated from 34 breast cancer patients, and then the role of ABCC5 in mediating transport of pemetrexed and apoptosis pathway in MCF-7 cell lines was assessed. Finally, the functions of ABCC5 on therapeutic effect of pemetrexed was evaluated in breast cancer bearing mice.ResultsThe expressions of ABCC2, ABCC4, ABCC5 and ABCG2 were significantly increased in pan-resistance cell lines, and the ABCC5, the most obvious one, was 5.21 times higher than that of the control group. The expression of ABCC5 was inversely correlated with sensitivity (IC50) of pemetrexed (r = 0.741; p<0.010) in breast cancer cell lines from 34 patients. Further, we found expression of ABCC5 influenced the efflux and cytotoxicity of pemetrexed in MCF-7 cell line, and the IC50 were 0.06 μg/ml and 0.20 μg/ml in ABCC5 knock-down and over-expression cells, respectively. In vivo study, we found ABCC5 affected sensitivity of pemetrexed in breast cancer bearing mice, and the tumor volume was much larger in ABCC5 over-expression group than that in control group (2.7 folds vs 1.2 folds).ConclusionsOur results indicated ABCC5 was associated with pemetrexed sensitivity and resistance in vitro and in vivo, and may be a biomarker for regimen optimization of pemetrexed in breast cancer treatment.

scholarly journals Novel Mechanisms of Tumor Promotion by the Insulin Receptor Isoform A in Triple-Negative Breast Cancer Cells

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3145
Author(s):  
Veronica Vella ◽  
Marika Giuliano ◽  
Alessandro La Ferlita ◽  
Michele Pellegrino ◽  
Germano Gaudenzi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Insulin Receptor ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Biological Effects ◽  
Tumor Biology ◽  
Endogenous Insulin

The insulin receptor isoform A (IR-A) plays an increasingly recognized role in fetal growth and tumor biology in response to circulating insulin and/or locally produced IGF2. This role seems not to be shared by the IR isoform B (IR-B). We aimed to dissect the specific impact of IR isoforms in modulating insulin signaling in triple negative breast cancer (TNBC) cells. We generated murine 4T1 TNBC cells deleted from the endogenous insulin receptor (INSR) gene and expressing comparable levels of either human IR-A or IR-B. We then measured IR isoform-specific in vitro and in vivo biological effects and transcriptome in response to insulin. Overall, the IR-A was more potent than the IR-B in mediating cell migration, invasion, and in vivo tumor growth. Transcriptome analysis showed that approximately 89% of insulin-stimulated transcripts depended solely on the expression of the specific isoform. Notably, in cells overexpressing IR-A, insulin strongly induced genes involved in tumor progression and immune evasion including chemokines and genes related to innate immunity. Conversely, in IR-B overexpressing cells, insulin predominantly induced the expression of genes primarily involved in the regulation of metabolic pathways and, to a lesser extent, tumor growth and angiogenesis.

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