Publications by authors named "Mona Mostafa Mohamed"

19 Publications

  • Page 1 of 1

IL-8 secreted by tumor associated macrophages contribute to lapatinib resistance in HER2-positive locally advanced breast cancer via activation of Src/STAT3/ERK1/2-mediated EGFR signaling.

Biochim Biophys Acta Mol Cell Res 2021 May 2;1868(6):118995. Epub 2021 Mar 2.

Zoology Department, Faculty of Science, Cairo University, Giza 12613, Egypt; Director of Biotechnology program, Faculty of Science, Galala University, 43511 Suez, Egypt. Electronic address:

Locally advanced breast cancer (LABC) is an aggressive disease characterized by late clinical presentation, large tumor size, treatment resistance and low survival rate. Expression of EGFR/HER2 and activation of intracellular tyrosine kinase domains in LABC are associated with poor prognosis. Thus, target therapies such as the anti-receptor tyrosine kinases lapatinib drug have been more developed in the past decade. The response to lapatinib involves the inhibition of RTKs and subsequently signaling molecules such as Src/STAT3/Erk1/2 known also to be activated by the cytokines in the tumor microenvironment (TME). The aim of the present study is to identify the major cytokine that might contribute to lapatinib resistance in EGFR+/HER2+ LABC patients. Indeed, tumor associated macrophages (TAMs) are the main source of cytokines in the TME. Herein, we isolated TAMs from LABC during modified radical mastectomy (MRM). Cytokine profile of TAMs revealed that IL-8 is the most prominent highly secreted cytokine by TAMs of LABC patients. Using in-vitro cell culture model we showed that recombinant IL-8 (50 and 100 ng/mL) at different time intervals interfere with lapatinib action via activation of Src/EGFR and signaling molecules known to be inhibited during treatment. We proposed that to improve LABC patients' response to lapatinib treatment it is preferred to use combined therapy that neutralize or block the action of IL-8.
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http://dx.doi.org/10.1016/j.bbamcr.2021.118995DOI Listing
May 2021

IL-8 and MCP-1/CCL2 regulate proteolytic activity in triple negative inflammatory breast cancer a mechanism that might be modulated by Src and Erk1/2.

Toxicol Appl Pharmacol 2020 08 5;401:115092. Epub 2020 Jun 5.

Department of Zoology, Faculty of Science, Cairo University, Giza 12613, Egypt. Electronic address:

Inflammatory breast cancer (IBC) is a highly metastatic and lethal breast cancer. As many as 25-30% of IBCs are triple negative (TN) and associated with low survival rates and poor prognosis. We found that the microenvironment of IBC is characterized by high infiltration of tumor associated macrophages (TAMs) and by over-expression of the cysteine protease cathepsin B (CTSB). TAMs in IBC secrete high levels of the cytokines interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1/CCL2) compared to non-IBC patients. Herein, we tested the roles of IL-8 and MCP-1/CCL2 in modulating proteolytic activity and invasiveness of TN-non-IBC as compared to TN-IBC and addressed the underlying molecular mechanism(s) for both cytokines. Quantitative real time PCR results showed that IL-8 and MCP-1/CCL2 were significantly overexpressed in tissues of TN-IBCs. IL-8 and MCP-1/CCL2 induced CTSB expression and activity of the p-Src and p-Erk1/2 signaling pathways relevant for invasion and metastasis in TN-non-IBC, HCC70 cells and TN-IBC, SUM149 cells. Dasatinib, an inhibitor of p-Src, and U0126, an inhibitor of p-Erk1/2, down-regulated invasion and expression of CTSB by HCC70 and SUM149 cells, a mechanism that is reversed by IL-8 and MCP-1/CCL2. Our study shows that targeting the cytokines IL-8 and MCP-1/CCL2 and associated signaling molecules may represent a promising therapeutic strategy in TN-IBC patients.
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http://dx.doi.org/10.1016/j.taap.2020.115092DOI Listing
August 2020

The immunomodulatory role of tumor Syndecan-1 (CD138) on ex vivo tumor microenvironmental CD4+ T cell polarization in inflammatory and non-inflammatory breast cancer patients.

PLoS One 2019 30;14(5):e0217550. Epub 2019 May 30.

Department of Zoology, Faculty of Science, Cairo University, Giza, Egypt.

Herein, we aimed to identify the immunomodulatory role of tumor Syndecan-1 (CD138) in the polarization of CD4+ T helper (Th) subsets isolated from the tumor microenvironment of inflammatory breast cancer (IBC) and non-IBC patients. Lymphocytes and mononuclear cells isolated from the axillary tributaries of non-IBC and IBC patients during modified radical mastectomy were either stimulated with the secretome as indirect co-culture or directly co-cultured with control and Syndecan-1-silenced SUM-149 IBC cells. In addition, peripheral blood mononuclear cells (PBMCs) of normal subjects were used for the direct co-culture. Employing flow cytometry, we analyzed the expression of the intracellular IFN-γ, IL-4, IL-17, and Foxp3 markers as readout for basal and co-cultured Th1, Th2, Th17, and Treg CD4+ subsets, respectively. Our data revealed that IBC displayed a lower basal frequency of Th1 and Th2 subsets than non-IBC. Syndecan-1-silenced SUM-149 cells significantly upregulated only Treg subset polarization of normal subjects relative to controls. However, Syndecan-1 silencing significantly enhanced the polarization of Th17 and Treg subsets of non-IBC under both direct and indirect conditions and induced only Th1 subset polarization under indirect conditions compared to control. Interestingly, qPCR revealed that there was a negative correlation between Syndecan-1 and each of IL-4, IL-17, and Foxp3 mRNA expression in carcinoma tissues of IBC and that the correlation was reversed in non-IBC. Mechanistically, Syndecan-1 knockdown in SUM-149 cells promoted Th17 cell expansion via upregulation of IL-23 and the Notch ligand DLL4. Overall, this study indicates a low frequency of the circulating antitumor Th1 subset in IBC and suggests that tumor Syndecan-1 silencing enhances ex vivo polarization of CD4+ Th17 and Treg cells of non-IBC, whereby Th17 polarization is possibly mediated via upregulation of IL-23 and DLL4. These findings suggest the immunoregulatory role of tumor Syndecan-1 expression in Th cell polarization that may have therapeutic implications for breast cancer.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0217550PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6542534PMC
February 2020

Tumor microenvironmental plasmacytoid dendritic cells contribute to breast cancer lymph node metastasis via CXCR4/SDF-1 axis.

Breast Cancer Res Treat 2019 Apr 10;174(3):679-691. Epub 2019 Jan 10.

Department of Zoology, Faculty of Science, Cairo University, 12613, Giza, Egypt.

Purpose: Plasmacytoid dendritic cells (PDCs) infiltration into breast cancer tissues is associated with poor prognosis. Also, CXCR4 shows compelling evidences to be exploited by cancer cells to migrate to distant sites. The present study investigated lymph node metastasis in the light of PDCs infiltration and the potential cross talk with CXCR4/SDF-1 chemokine axis.

Methods: We assessed circulating PDCs proportions drained from the axillary tributaries, and the in situ expression of both CD303 and CXCR4 in breast cancer patients with positive lymph nodes (pLN) and negative lymph nodes (nLN) using immunohistochemistry and flow cytometry. We also analyzed the expression of SDF-1 in lymph nodes of pLN and nLN patients. We studied the effect of the secretome of PDCs of pLN and nLN patients on the expression of CXCR4 and activation of NF-κB in human breast cancer cell lines SKBR3 and MCF-7. TNF-α mRNA expression level in PDCs from both groups was determined by qPCR.

Results: Our findings indicate increased infiltration of PDCs in breast cancer tissues of pLN patients than nLN patients, which correlates with CXCR4 cells percentage. Interestingly, SDF-1 is highly immunostained in lymph nodes of pLN patients compared to nLN patients. Our in vitro experiments demonstrate an upregulation of NF-κB expression and CXCR4 cells upon stimulation with PDCs secretome of pLN patients than those of nLN patients. Also, PDCs isolated from pLN patients exhibited a higher TNF-α mRNA expression than nLN patients. Treatment of MCF-7 cell lines with TNF-α significantly upregulates CXCR4 expression.

Conclusions: Our findings suggest a potential role for microenvironmental PDCs in breast cancer lymph node metastasis via CXCR4/SDF-1 axis.
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http://dx.doi.org/10.1007/s10549-019-05129-8DOI Listing
April 2019

Anti-proliferative effect of chitosan nanoparticles (extracted from crayfish Procambarus clarkii, Crustacea: Cambaridae) against MDA-MB-231 and SK-BR-3 human breast cancer cell lines.

Int J Biol Macromol 2019 Apr 17;126:478-487. Epub 2018 Dec 17.

Cancer Cell Biology, Zoology Department, Faculty of Science, Cairo University, Giza, Egypt.

Actually, the most common cancer in women is the breast cancer which is the second most widespread cancer overall. In 2018, there were over two million new cases of women breast cancer. Particularly, we tried to extract chitosan from crayfish Procambarus clarkii, Crustacea: Cambaridae, by N-deacetylation of chitin. The chemical structure of chitosan was characterized by Fourier transform infrared (FT-IR) spectroscopy. Also DDA was calculated from FT-IR and ultraviolet spectrophotometry data. Chitosan nanoparticles were prepared using a ball-milling technique. The as-prepared chitosan nanoparticles were characterized by transmission electron microscopy, dynamic light scattering as well as zeta potential. The cytotoxicity of chitosan and its nanoparticles (50 and 100 μg/mL) against human breast cancer (SK BR3 and MDA-MB-231 cell lines) was evaluated. MTT assay asserts the significant inhibitory action of both chitosan and its nanoparticles on the proliferation of human breast cancer cells in vitro. Chitosan nanoparticles had more anti-proliferative effects on MDA-MB-231 and SK-BR-3 cell lines than its corresponding chitosan. Although, chitosan nanoparticles, that has higher DDA, had a higher cytotoxic activity against human breast cancer MDA-MB-231 and SK-BR-3 cell lines in vitro. Eventually, chitosan and its nanoparticles can be considered as a promising natural compounds in human breast cancer treatment.
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http://dx.doi.org/10.1016/j.ijbiomac.2018.12.151DOI Listing
April 2019

Characterization of inflammatory breast cancer: a vibrational microspectroscopy and imaging approach at the cellular and tissue level.

Analyst 2018 Dec;143(24):6103-6112

Université de Reims Champagne-Ardenne, Laboratoire de Biochimie Médicale et de Biologie Moléculaire, UFR de Médecine, Reims, France.

Inflammatory breast cancer (IBC) has a poor prognosis because of the lack of specific biomarkers and its late diagnosis. An accurate and rapid diagnosis implemented early enough can significantly improve the disease outcome. Vibrational spectroscopy has proven to be useful for cell and tissue characterization based on the intrinsic molecular information. Here, we have applied infrared and Raman microspectroscopy and imaging to differentiate between non-IBC and IBC at both cell and tissue levels. Two human breast cancer cell lines (MDA-MB-231 and SUM-149), 20 breast cancer patients (10 non-IBC and 10 IBC), and 4 healthy volunteer biopsies were investigated. Fixed cells and tissues were analyzed by FTIR microspectroscopy and imaging, while live cells were studied by Raman microspectroscopy. Spectra were analyzed by hierarchical cluster analysis (HCA) and images by common k-means clustering algorithms. For both cell suspensions and single cells, FTIR spectroscopy showed sufficient high inter-group variability to delineate MDA-MB-231 and SUM-149 cell lines. Most significant differences were observed in the spectral regions of 1096-1108 and 1672-1692 cm-1. Analysis of live cells by Raman microspectroscopy gave also a good discrimination of these cell types. The most discriminant regions were 688-992, 1019-1114, 1217-1375 and 1516-1625 cm-1. Finally, k-means cluster analysis of FTIR images allowed delineating non-IBC from IBC tissues. This study demonstrates the potential of vibrational spectroscopy and imaging to discriminate between non-IBC and IBC at both cell and tissue levels.
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http://dx.doi.org/10.1039/c8an01292jDOI Listing
December 2018

IL-10 correlates with the expression of carboxypeptidase B2 and lymphovascular invasion in inflammatory breast cancer: The potential role of tumor infiltrated macrophages.

Curr Probl Cancer 2018 Mar - Apr;42(2):215-230. Epub 2018 Jan 10.

Department of Zoology, Faculty of Science, Cairo University, Giza, Egypt; Breast-Gynecological International Cancer Society, Cairo, Egypt. Electronic address:

Pro-carboxypeptidase B2 (pro-CPB2) or thrombin-activatable fibrinolysis inhibitor (TAFI) is a glycoprotein encoded by the CPB2 gene and deregulated in several cancer types, including breast cancer. Thrombin binding to thrombomodulin (TM), encoded by THBD, is important for TAFI activation. CPB2 gene expression is influenced by genetic polymorphism and cytokines such as interleukin 10 (IL-10). Our previous results showed that tumor infiltrating monocytes/macrophages (CD14/CD16) isolated from inflammatory breast cancer (IBC) patients' secrete high levels of IL-10. The aim of the present study is to test genetic polymorphism and expression of CPB2 in healthy breast tissues and carcinoma tissues of non-IBC and IBC patients. Furthermore, to investigate whether IL-10 modulates the expression of CPB2 and THBD in vivo and in-vitro. We tested CPB2 Thr325Ile polymorphism using restriction fragment length polymorphism, (RFLP) technique in healthy and carcinoma breast tissues. The mRNA expression of CPB2, THBD and IL10 were assessed by RT-qPCR. Infiltration of CD14 cells was assessed by immunohistochemistry. In addition, we investigated the correlation between infiltration of CD14 cells and expression of IL10 and CPB2. Furthermore, we correlated IL10 expression with the expression of both CPB2 and THBD in breast carcinoma tissues. Finally, we validated the role of recombinant IL-10 in regulating the expression of CPB2 and THBD using different breast cancer cell lines. Our results showed that CPB2 genotypes carrying the high-risk allele [Thr/Ile (CT) and Ile/Ile (TT)] were more frequent in both IBC and non-IBC patients compared to control group. CPB2 genotypes did not show any statistical correlation with CPB2 mRNA expression levels or patients' clinical pathological properties. Interestingly, CPB2 and IL10 expression were significantly higher and positively correlated with the incidence of CD14 cells in carcinoma tissues of IBC as compared to non-IBC. On the other hand, THBD expression was significantly lower in IBC carcinoma versus non-IBC tissues. Based on molecular subtypes, CPB2 and IL10 expression were significantly higher in triple negative (TN) as compared to hormonal positive (HP) carcinoma tissues of IBC. Moreover, CPB2 expression was positively correlated with presence of lymphovascular invasion and the expression of IL10 in carcinoma tissues of IBC patients. Furthermore, recombinant human IL-10 stimulated CPB2 expression in SUM-149 (IBC cell line) but not in MDA-MB-231 (non-IBC cell line), while there was no significant effect THBD expression. In conclusion, carcinoma tissues of IBC patients are characterized by higher expression of CPB2 and lower expression of THBD. Moreover, CPB2 positively correlates with IL10 mRNA expression, incidence of CD14 cells and lymphovascular invasion in IBC patients. IL-10 stimulated CPB2 expression in TN-IBC cell line suggests a relevant role of CPB2 in the aggressive phenotype of IBC.
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http://dx.doi.org/10.1016/j.currproblcancer.2018.01.009DOI Listing
April 2019

Syndecan-1 is a novel molecular marker for triple negative inflammatory breast cancer and modulates the cancer stem cell phenotype via the IL-6/STAT3, Notch and EGFR signaling pathways.

Mol Cancer 2017 03 7;16(1):57. Epub 2017 Mar 7.

Department of Gynecology and Obstetrics, Münster University Hospital, Albert-Schweitzer-Campus 1, D11, 48149, Münster, Germany.

Background: Inflammatory breast cancer (IBC), a particularly aggressive form of breast cancer, is characterized by cancer stem cell (CSC) phenotype. Due to a lack of targeted therapies, the identification of molecular markers of IBC is of major importance. The heparan sulfate proteoglycan Syndecan-1 acts as a coreceptor for growth factors and chemokines, modulating inflammation, tumor progression, and cancer stemness, thus it may emerge as a molecular marker for IBC.

Methods: We characterized expression of Syndecan-1 and the CSC marker CD44, Notch-1 & -3 and EGFR in carcinoma tissues of triple negative IBC (n = 13) and non-IBC (n = 17) patients using qPCR and immunohistochemistry. Impact of siRNA-mediated Syndecan-1 knockdown on the CSC phenotype of the human triple negative IBC cell line SUM-149 and HER-2-overexpressing non-IBC SKBR3 cells employing qPCR, flow cytometry, Western blotting, secretome profiling and Notch pharmacological inhibition experiments. Data were statistically analyzed using Student's t-test/Mann-Whitney U-test or one-way ANOVA followed by Tukey's multiple comparison tests.

Results: Our data indicate upregulation and a significant positive correlation of Syndecan-1 with CD44 protein, and Notch-1 & -3 and EGFR mRNA in IBC vs non-IBC. ALDH1 activity and the CD44CD24 subset as readout of a CSC phenotype were reduced upon Syndecan-1 knockdown. Functionally, Syndecan-1 silencing significantly reduced 3D spheroid and colony formation. Intriguingly, qPCR results indicate downregulation of the IL-6, IL-8, CCL20, gp130 and EGFR mRNA upon Syndecan-1 suppression in both cell lines. Moreover, Syndecan-1 silencing significantly downregulated Notch-1, -3, -4 and Hey-1 in SUM-149 cells, and downregulated only Notch-3 and Gli-1 mRNA in SKBR3 cells. Secretome profiling unveiled reduced IL-6, IL-8, GRO-alpha and GRO a/b/g cytokines in conditioned media of Syndecan-1 knockdown SUM-149 cells compared to controls. The constitutively activated STAT3 and NFκB, and expression of gp130, Notch-1 & -2, and EGFR proteins were suppressed upon Syndecan-1 ablation. Mechanistically, gamma-secretase inhibition experiments suggested that Syndecan-1 may regulate the expression of IL-6, IL-8, gp130, Hey-1, EGFR and p-Akt via Notch signaling.

Conclusions: Syndecan-1 acts as a novel tissue biomarker and a modulator of CSC phenotype of triple negative IBC via the IL-6/STAT3, Notch and EGFR signaling pathways, thus emerging as a promising therapeutic target for IBC.
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http://dx.doi.org/10.1186/s12943-017-0621-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5341174PMC
March 2017

Secretome of tumor-associated leukocytes augment epithelial-mesenchymal transition in positive lymph node breast cancer patients via activation of EGFR/Tyr845 and NF-κB/p65 signaling pathway.

Tumour Biol 2016 Sep 22;37(9):12441-12453. Epub 2016 Jun 22.

Department of Zoology, Faculty of Science, Cairo University, Giza, 12613, Egypt.

Epithelial-mesenchymal transition (EMT) is an essential process in breast cancer metastasis. The aim of the present study was to determine the role of secretions of tumor-associated leukocytes (TALs) isolated from negative and positive lymph nodes (nLNs and pLNs, respectively) breast cancer patients in regulating EMT mechanism and the associated signaling pathways. We found an increased infiltration of TALs, which was associated with downregulation of E-cadherin and over-expression of vimentin in the breast carcinoma tissues of pLNs as compared to nLNs patients and normal breast tissues obtained from healthy volunteers during mammoplasty. Furthermore, TALs isolated from pLNs breast cancer patients secreted an elevated panel of cytokines by up to 2-5-fold when compared with those isolated from nLNs patients. Secretome of TALs of pLNs possessed higher TARC, IGF-1, IL-3, TNF-β, IL-5, G-CSF, IL-4, and IL-1α with more than a fivefold compared to those of nLNs. Using the human breast cancer cell lines MCF-7 and MDA-MB-231, we found that cytokines secreted by TALs isolated from nLNs and pLNs breast cancer patients promoted EMT via upregulation of TGF-β and vimentin and downregulation of E-cadherin at messenger RNA (mRNA) levels in both cell lines and at protein level in MCF-7. While TGF-β is over-expressed by MDA-MB-231 seeded in media conditioned by secretome of TALs isolated from nLNs and pLNs breast cancer patients. The downstream TGF-β signaling transcription factors, Snail, Slug, and Twist, known to be associated with EMT mechanism were over-expressed by MCF-7 and MDA-MB-231 seeded in media conditioned by secretome of TALs isolated from nLNs and pLNs breast cancer patients. Acquisition of EMT in MCF-7 cells is mechanistically attributed to the activation of EGFR and NF-κB/p65 signaling which are significantly highly expressed by MCF-7 cells seeded in media conditioned by secretome of TALs isolated from pLNs compared to nLNs patients. Overall, this study provides implications of secretome of TALs and activated EGFR and NF-κB/p65 in EMT process that may be considered a therapeutic strategy to inhibit lymph node metastasis in breast cancer patients.
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http://dx.doi.org/10.1007/s13277-016-5123-xDOI Listing
September 2016

Assessing the Awareness of Egyptian Medical Students about Responsible Conduct of Research and Research Ethics: Impact of an Educational Campaign.

Account Res 2016 ;23(4):199-218

e Department of Zoology, Faculty of Science , Cairo University , Giza , Egypt.

This is a quasi-experimental pre-post assessment study utilizing an anonymous self-administered questionnaire to assess Egyptian medical students' awareness about responsible conduct of research (RCR) and research ethics. Students' were assessed before and after an RCR awareness campaign. Our results showed that most of the pre-campaign respondents were not familiar with the basic principles and terms of RCR. An increase in the awareness about RCR across all discussed topics was noted following the campaign. We concluded that an educational awareness campaign is effective in increasing medical students' awareness about RCR and should be incorporated into current medical school curricula in Egypt.
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http://dx.doi.org/10.1080/08989621.2015.1127762DOI Listing
February 2017

Inflammatory and Non-inflammatory Breast Cancer: A Potential Role for Detection of Multiple Viral DNAs in Disease Progression.

Ann Surg Oncol 2016 Feb 27;23(2):494-502. Epub 2015 Oct 27.

Cancer Biology Research Lab, Department of Zoology, Faculty of Science, Cairo University, Giza, Egypt.

Background: Inflammatory breast cancer (IBC) is the most lethal form of breast cancer. Multiple viral infections in IBC tissues were found to be associated with disease pathogenesis.

Objective: The aim of the present study was to correlate the incidence of viral DNA with breast cancer progression.

Materials And Methods: Overall, 135 women diagnosed with breast cancer were enrolled in this study. Using polymerase chain reaction and sequencing assays, we determined the incidence of human papillomavirus types 16 and 18 (HPV-16 and -18), human cytomegalovirus (HCMV), Epstein-Barr virus, human herpes simplex virus type 1 and 2, and human herpes virus type 8 (HHV-8) in breast carcinoma tissue biopsies. We also assessed the expression of the cell proliferation marker Ki-67 by immunohistochemistry in association with the incidence of viral DNA.

Results: HCMV and HPV-16 were the most detected viral DNAs in breast carcinoma tissues; however, the frequency of HCMV and HHV-8 DNA were significantly higher in IBC than non-IBC tissues. Moreover, the prevalence of multiple viral DNAs was higher in IBC than non-IBC tissues. The incidence of multiple viral DNAs positively correlates with tumor size and number of metastatic lymph nodes in both non-IBC and IBC patients. The expression of Ki-67 was found to be significantly higher in both non-IBC and IBC tissues in which multiple viral DNAs were detected.

Conclusions: The incidence of multiple viral DNAs in IBC tissues was higher compared with non-IBC tissues. The present results suggest the possibility of a functional relationship between the presence of multiple viral DNAs and disease pathogenesis.
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http://dx.doi.org/10.1245/s10434-015-4888-2DOI Listing
February 2016

Inflammatory breast cancer: high incidence of detection of mixed human cytomegalovirus genotypes associated with disease pathogenesis.

Front Oncol 2014 11;4:246. Epub 2014 Sep 11.

Department of Zoology, Faculty of Science, Cairo University , Giza , Egypt.

Inflammatory breast cancer (IBC) is a highly metastatic, aggressive, and fatal form of breast cancer. Patients presenting with IBC are characterized by a high number of axillary lymph node metastases. Recently, we found that IBC carcinoma tissues contain significantly higher levels of human cytomegalovirus (HCMV) DNA compared to other breast cancer tissues that may regulate cell signaling pathways. In fact, HCMV pathogenesis and clinical outcome can be statistically associated with multiple HCMV genotypes within IBC. Thus, in the present study, we established the incidence and types of HCMV genotypes present in carcinoma tissues of infected non-IBC versus IBC patients. We also assessed the correlation between detection of mixed genotypes of HCMV and disease progression. Genotyping of HCMV in carcinoma tissues revealed that glycoprotein B (gB)-1 and glycoprotein N (gN)-1 were the most prevalent HCMV genotypes in both non-IBC and IBC patients with no significant difference between patients groups. IBC carcinoma tissues, however, showed statistically significant higher incidence of detection of the gN-3b genotype compared to non-IBC patients. The incidence of detection of mixed genotypes of gB showed that gB-1 + gB-3 was statistically significantly higher in IBC than non-IBC patients. Similarly, the incidence of detection of mixed genotypes of gN showed that gN-1 + gN-3b and gN-3 + gN-4b/c were statistically significant higher in the carcinoma tissues of IBC than non-IBC. Mixed presence of different HCMV genotypes was found to be significantly correlated with the number of metastatic lymph nodes in non-IBC but not in IBC patients. In IBC, detection of mixed HCMV different genotypes significantly correlates with lymphovascular invasion and formation of dermal lymphatic emboli, which was not found in non-IBC patients.
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http://dx.doi.org/10.3389/fonc.2014.00246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4160966PMC
October 2014

Human cytomegalovirus infection enhances NF-κB/p65 signaling in inflammatory breast cancer patients.

PLoS One 2013 13;8(2):e55755. Epub 2013 Feb 13.

Department of General Surgery, Faculty of Medicine, Ain Shams University, Cairo, Egypt.

Human Cytomegalovirus (HCMV) is an endemic herpes virus that re-emerges in cancer patients enhancing oncogenic potential. Recent studies have shown that HCMV infection is associated with certain types of cancer morbidity such as glioblastoma. Although HCMV has been detected in breast cancer tissues, its role, if any, in the etiology of specific forms of breast cancer has not been investigated. In the present study we investigated the presence of HCMV infection in inflammatory breast cancer (IBC), a rapidly progressing form of breast cancer characterized by specific molecular signature. We screened for anti-CMV IgG antibodies in peripheral blood of 49 non-IBC invasive ductal carcinoma (IDC) and 28 IBC patients. In addition, we screened for HCMV-DNA in postsurgical cancer and non-cancer breast tissues of non-IBC and IBC patients. We also tested whether HCMV infection can modulate the expression and activation of transcriptional factor NF-κB/p65, a hallmark of IBC. Our results reveal that IBC patients are characterized by a statistically significant increase in HCMV IgG antibody titers compared to non-IBC patients. HCMV-DNA was significantly detected in cancer tissues than in the adjacent non-carcinoma tissues of IBC and IDC, and IBC cancer tissues were significantly more infected with HCMV-DNA compared to IDC. Further, HCMV sequence analysis detected different HCMV strains in IBC patients tissues, but not in the IDC specimens. Moreover, HCMV-infected IBC cancer tissues were found to be enhanced in NF-κB/p65 signaling compared to non-IBC patients. The present results demonstrated a correlation between HCMV infection and IBC. Etiology and causality of HCMV infection with IBC now needs to be rigorously examined.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0055755PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3572094PMC
August 2013

Membrane type-1 matrix metalloproteinase (MT1-MMP) correlates with the expression and activation of matrix metalloproteinase-2 (MMP-2) in inflammatory breast cancer.

Int J Clin Exp Med 2011 11;4(4):265-75. Epub 2011 Oct 11.

Department ofZoology, Faculty of Science- Sana'a University, Yemen.

Inflammatory breast cancer (IBC) represents the most aggressive form of breast cancer, characterized by rapid progression, involvement of dermal lymphatic emboli and extensive metastatic lymph nodes. Matrix metalloproteinases (MMPs) are proteolytic enzymes that play an important role in cancer invasion and metastasis. Although the role of MMPs in non-IBC is well studied, little is known about its role in IBC. Thus the goal of the present study was to 1) investigate the expression and activity levels of membrane type matrix metalloproteinase-1 (MT1-MMP) and matrix metalloproteinase-2 and-9 (MMP-2 and MMP-9) in IBC versus non-IBC tissue samples and; 2) test correlation between expression of MT1-MMP and pro- and active forms of MMP-2 and MMP-9. We enrolled 51 breast cancer patients, 21 were diagnosed as IBC and 30 as non-IBC. Level of expression of MT1-MMP in carcinoma tissue was assessed by immunoblot and immunohistochemistry techniques. The expression and activation of MMP-2 and MMP-9 was measured by gelatin zymography. Our results revealed that MT1-MMP, pro-MMP-2, pro-MMP-9 and active MMP-2 were more expressed in IBC tissue versus non-IBC. Furthermore, we found that MT1-MMP expression correlates with expression of pro-MMP-2, pro-MMP-9 and active MMP-2 in IBC tissue samples and with MMP-9 in non-IBC tissue sample. In conclusion, our study suggests a role of MT1-MMP in inflammatory breast cancer disease progression.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3228582PMC
January 2012

Capturing and characterizing immune cells from breast tumor microenvironment: an innovative surgical approach.

Ann Surg Oncol 2010 Oct 24;17(10):2677-84. Epub 2010 Mar 24.

Department of General Surgery, Faculty of Medicine, Ain Shams University, Cairo, Egypt.

Background: In breast cancer patients, venous drainage of the breast may contain cells of immunological importance, tumor cells undergoing dissemination, and other biological factors derived from the tumor microenvironment. Collecting axillary venous blood during modified radical mastectomy and thus before dilution in the circulation may allow us to define biological properties of the tumor microenvironment. Aims were to (1) develop a surgical approach to collect blood from the breast tumor microenvironment through tributaries of the axillary vein and (2) characterize and compare immune cells collected from the axillary vein with those in peripheral blood of breast cancer patients.

Materials And Methods: We enrolled 17 women aged 30-50 years and diagnosed with breast cancer by mammography, ultrasound, and biopsy (stages II-III). All patients were, preoperatively, treatment-naive. During routine surgical dissection, blood was collected in heparin tubes, 10 mL from tributaries of the axillary vein and 10 mL from peripheral blood. Mononuclear cells were separated, and percentages of different leukocyte populations were determined by flow cytometry.

Results: We detected a significant increase in the percentage of total T lymphocytes and T helper cells collected from axillary tributaries, but not in the percentages of cytotoxic T cells, monocytes, natural killer, or B cells compared with peripheral blood.

Conclusions: The present study validated using an intraoperative surgical approach to collect leukocytes drained from the tumor microenvironment through axillary tributaries. Our results showed an increase in the infiltration of total T-lymphocytes and T helper cells in the tumor microenvironment, suggesting that they may contribute to tumor pathogenesis.
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http://dx.doi.org/10.1245/s10434-010-1029-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3402355PMC
October 2010

Human monocytes augment invasiveness and proteolytic activity of inflammatory breast cancer.

Biol Chem 2008 Aug;389(8):1117-21

Department of Zoology, Faculty of Science, Cairo University, 12613 Cairo, Egypt.

Inflammatory breast cancer (IBC) is the most aggressive form of breast cancer, and here, we examined in vitro the interactions between the human IBC cell line SUM149 and U937 human naive monocytes. We found an altered morphology, enhanced invasiveness and proteolytic activity of SUM149 cells when cultured with U937 cells or in U937-conditioned media (U937-CM). Increases in expression and activity of the cysteine protease cathepsin B and expression of caveolin-1 were also detected in SUM149 cells grown in U937-CM, thus suggesting a contribution of these proteins to the augmented invasion through and proteolysis of the extracellular matrix by the IBC cells.
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http://dx.doi.org/10.1515/BC.2008.117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3402350PMC
August 2008

Cysteine cathepsins: multifunctional enzymes in cancer.

Nat Rev Cancer 2006 Oct;6(10):764-75

Department of Pharmacology, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.

Cysteine cathepsins are highly upregulated in a wide variety of cancers by mechanisms ranging from gene amplification to post-transcriptional modification. Their localization within intracellular lysosomes often changes during neoplastic progression, resulting in secretion of both inactive and active forms and association with binding partners on the tumour cell surface. Secreted, cell-surface and intracellular cysteine cathepsins function in proteolytic pathways that increase neoplastic progression. Direct proof for causal roles in tumour growth, migration, invasion, angiogenesis and metastasis has been shown by downregulating or ablating the expression of individual cysteine cathepsins in tumour cells and in transgenic mouse models of human cancer.
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http://dx.doi.org/10.1038/nrc1949DOI Listing
October 2006

Anti-malarial chloroquine stimulate p53-apoptotic pathway in rat hepatocytes.

J Egypt Soc Parasitol 2005 Apr;35(1):19-32

Department of Zoology, Faculty of Science, Cairo University, Egypt.

The study investigated rat liver injury produced by anti-malarial dose of chloroquine (CQ) and to elucidate if CQ could induce DNA damage and subsequently p53-dependent apoptosis in rat hepatocytes or not. The effect of anti-malarial CQ on p53-apoptotic pathway of rat liver cells after different time intervals (1, 2 & 3 days) was studied. Apoptosis was assessed in whole liver tissue using ELISA technique and at single cell level using TUNEL technique. The level of expression of p53 was measureed quantitatively by ELISA. Results found that CQ induced DNA damage and rat hepatocytes apoptosis in a time dependent manner. Secondly, p53 expression was associated with CQ administration in time dependent manner. Thus, anti-malarial dose of CQ induces DNA damage and apoptosis of rat liver cells and the expression of p53 could be considered as a normal response of hepatocytes suffering from CQ genotoxic stress.
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April 2005