Publications by authors named "Lamiaa El-Shennawy"

10 Publications

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ICAM1 initiates CTC cluster formation and trans-endothelial migration in lung metastasis of breast cancer.

Nat Commun 2021 08 11;12(1):4867. Epub 2021 Aug 11.

Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Circulating tumor cell (CTC) clusters mediate metastasis at a higher efficiency and are associated with lower overall survival in breast cancer compared to single cells. Combining single-cell RNA sequencing and protein analyses, here we report the profiles of primary tumor cells and lung metastases of triple-negative breast cancer (TNBC). ICAM1 expression increases by 200-fold in the lung metastases of three TNBC patient-derived xenografts (PDXs). Depletion of ICAM1 abrogates lung colonization of TNBC cells by inhibiting homotypic tumor cell-tumor cell cluster formation. Machine learning-based algorithms and mutagenesis analyses identify ICAM1 regions responsible for homophilic ICAM1-ICAM1 interactions, thereby directing homotypic tumor cell clustering, as well as heterotypic tumor-endothelial adhesion for trans-endothelial migration. Moreover, ICAM1 promotes metastasis by activating cellular pathways related to cell cycle and stemness. Finally, blocking ICAM1 interactions significantly inhibits CTC cluster formation, tumor cell transendothelial migration, and lung metastasis. Therefore, ICAM1 can serve as a novel therapeutic target for metastasis initiation of TNBC.
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http://dx.doi.org/10.1038/s41467-021-25189-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8358026PMC
August 2021

EGFR inhibition blocks cancer stem cell clustering and lung metastasis of triple negative breast cancer.

Theranostics 2021 30;11(13):6632-6643. Epub 2021 Apr 30.

Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Triple-negative breast cancer (TNBC) is one of the most aggressive and metastatic breast cancer subtypes lacking targeted therapy. Our recent work demonstrated that circulating tumor cell (CTC) clusters and polyclonal metastasis of TNBC are driven by aggregation of CD44 cancer stem cells (CSC) and associated with an unfavorable prognosis, such as low overall survival. However, there is no existing therapeutic that can specifically block CTC or CSC cluster formation. Using patient-derived xenograft (PDX) models, we established an tumor cell clustering assay for a pilot screening of blockade antibodies. After identifying EGFR as a target candidate, we modulated the gene expression and inhibited its kinase activity to determine its functional importance in tumor cell clustering and therapeutic inhibition of lung metastasis. We also examined the molecular regulation network of EGFR and a potential connection to CSC marker CD44 and microRNAs, which regulate CTC clustering. We report here that EGFR inhibition successfully blocks circulating CSC (cCSC) clustering and lung metastasis of TNBC. EGFR enhances CD44-mediated tumor cell aggregation and CD44 stabilizes EGFR. Importantly, blocking EGFR by a novel anti-EGFR monoclonal antibody (clone LA1) effectively blocked cell aggregation and reduced lung metastasis . Furthermore, our data demonstrated that the tumor suppressor microRNA-30c serves as another negative regulator of cCSC clustering and lung metastasis by targeting CD44 as well as its downstream effector EGFR. Our studies identify a novel anti-EGFR therapeutic strategy to inhibit cCSC aggregation and therefore abolish cCSC cluster-mediated metastasis of TNBC.
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http://dx.doi.org/10.7150/thno.57706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120216PMC
July 2021

Dose-dependent reproductive toxicity of sodium benzoate in male rats: Inflammation, oxidative stress and apoptosis.

Reprod Toxicol 2020 12 7;98:92-98. Epub 2020 Sep 7.

Department Environmental Studies, Institute of Graduate Studies and Research, Alexandria University, Egypt. Electronic address:

The synthetic food preservative sodium benzoate (SB) is widely used in both food and pharmaceutical industries. A growing body of evidence highlights the adverse effects of SB on human health; however, effect of the prolonged intake of SB on the reproductive system is not fully elucidated. The current study investigates the effect of different doses of SB (0-1000 mg/kg BW) on the reproductive system of male rats administered oral SB for 90 consecutive days. Results revealed that increasing doses of SB significantly altered the weight of reproductive organs, decreased sperm count and motility and enhanced the percentage of abnormal sperms. This was concomitant with significant decline in plasma testosterone and FSH levels, increase in plasma LH and decrease in the activities of 17β-HSD and 17-KSR enzymes in the testes. Inflammation and oxidative stress were induced as indicated by the significant increase in TNF-α and IL-6 levels, inhibition of antioxidant enzymes activity and levels of GSH, increase in the levels of NO and TBARS and enhanced protein expression of mtTFA and UCP2 in the testes. Interestingly, p53 expression and caspase-3 activity were upregulated in the testes suggesting induction of apoptosis. Histopathological examination of the testes confirmed apoptosis and revealed degenerative alterations of the testes' architecture and perturbation of spermatogenesis. Based upon these findings, the no-observed-adverse-effect level of SB on the reproductive system was determined to be less than 1 mg/kg BW/day, highlighting the risks of long-term exposure to low as well as high doses of SB on male reproductive health.
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http://dx.doi.org/10.1016/j.reprotox.2020.08.014DOI Listing
December 2020

Mathematical Modelling for the Role of CD4T Cells in Tumor-Immune Interactions.

Comput Math Methods Med 2020 19;2020:7187602. Epub 2020 Feb 19.

Department of Engineering Mathematics and Physics, Faculty of Engineering, Alexandria University, Alexandria, Egypt.

Mathematical modelling has been used to study tumor-immune cell interaction. Some models were proposed to examine the effect of circulating lymphocytes, natural killer cells, and CD8T cells, but they neglected the role of CD4T cells. Other models were constructed to study the role of CD4T cells but did not consider the role of other immune cells. In this study, we propose a mathematical model, in the form of a system of nonlinear ordinary differential equations, that predicts the interaction between tumor cells and natural killer cells, CD4T cells, CD8T cells, and circulating lymphocytes with or without immunotherapy and/or chemotherapy. This system is stiff, and the Runge-Kutta method failed to solve it. Consequently, the "Adams predictor-corrector" method is used. The results reveal that the patient's immune system can overcome small tumors; however, if the tumor is large, adoptive therapy with CD4T cells can be an alternative to both CD8T cell therapy and cytokines in some cases. Moreover, CD4T cell therapy could replace chemotherapy depending upon tumor size. Even if a combination of chemotherapy and immunotherapy is necessary, using CD4T cell therapy can better reduce the dose of the associated chemotherapy compared to using combined CD8T cells and cytokine therapy. Stability analysis is performed for the studied patients. It has been found that all equilibrium points are unstable, and a condition for preventing tumor recurrence after treatment has been deduced. Finally, a bifurcation analysis is performed to study the effect of varying system parameters on the stability, and bifurcation points are specified. New equilibrium points are created or demolished at some bifurcation points, and stability is changed at some others. Hence, for systems turning to be stable, tumors can be eradicated without the possibility of recurrence. The proposed mathematical model provides a valuable tool for designing patients' treatment intervention strategies.
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http://dx.doi.org/10.1155/2020/7187602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049850PMC
January 2021

The Arabian camel, Camelus dromedarius interferon epsilon: Functional expression, in vitro refolding, purification and cytotoxicity on breast cancer cell lines.

PLoS One 2019 6;14(9):e0213880. Epub 2019 Sep 6.

Department of Biotechnology, Institute of Graduate Studies and Research, Alexandria University, Alexandria, Egypt.

The current study highlights, for the first time, cloning, overexpression and purification of the novel interferon epsilon (IFNƐ), from the Arabian camel Camelus dromedaries. The study then assesses the cytotoxicity of IFNε against two human breast cancer cell lines MDA-MB-231 and MCF-7. Full-length cDNA encoding interferon epsilon (IFNε) was isolated and cloned from the liver of the Arabian camel, C. dromedarius using reverse transcription-polymerase chain reaction. The sequence analysis of the camel IFNε cDNA showed a 582-bp open reading frame encoding a protein of 193 amino acids with an estimated molecular weight of 21.230 kDa. A BLAST search analysis revealed that the C. dromedarius IFNε shared high sequence identity with the IFN genes of other species, such as Camelus ferus, Vicugna pacos, and Homo sapiens. Expression of the camel IFNε cDNA in Escherichia coli gave a fusion protein band of 24.97 kDa after induction with either isopropyl β-D-1-thiogalactopyranoside or lactose for 5 h. Recombinant IFNε protein was overexpressed in the form of inclusion bodies that were easily solubilized and refolded using SDS and KCl. The solubilized inclusion bodies were purified to apparent homogeneity using nickel affinity chromatography. We examined the effect of IFNε on two breast cancer cell lines MDA-MB-231 and MCF-7. In both cell lines, IFNε inhibited cell survival in a dose dependent manner as observed by MTT assay, morphological changes and apoptosis assay. Caspase-3 expression level was found to be increased in MDA-MB-231 treated cells as compared to untreated cells.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0213880PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6730848PMC
March 2020

Coactivation of Estrogen Receptor and IKKβ Induces a Dormant Metastatic Phenotype in ER-Positive Breast Cancer.

Cancer Res 2018 02 11;78(4):974-984. Epub 2017 Dec 11.

Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, Illinois.

A growing body of evidence suggests that the inflammatory NFκB pathway is associated with the progression of ER tumors to more aggressive stages. However, it is unknown whether NFκB is a driver or a consequence of aggressive ER disease. To investigate this question, we developed breast cancer cell lines expressing an inducible, constitutively active form of IκB kinase β (CA-IKKβ), a key kinase in the canonical NFκB pathway. We found that CA-IKKβ blocked E2-dependent cell proliferation and tumor growth in a reversible manner, suggesting that IKKβ may contribute to tumor dormancy and recurrence of ER disease. Moreover, coactivation of ER and IKKβ promoted cell migration and invasion and drove experimental metastasis Gene expression profiling revealed a strong association between ER and CA-IKKβ-driven gene expression and clinically relevant invasion and metastasis gene signatures. Mechanistically, the invasive phenotype appeared to be driven by an expansion of a basal/stem-like cell population rather than EMT. Taken together, our findings suggest that coactivation of ER and the canonical NFκB pathway promotes a dormant, metastatic phenotype in ER breast cancer and implicates IKKβ as a driver of certain features of aggressive ER breast cancer. The canonical NFκB pathway promotes expansion of stem/basal-like cells and a dormant, metastatic phenotype in ER breast cancer cells. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-1686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5815896PMC
February 2018

Dimethyl Fumarate Inhibits the Nuclear Factor κB Pathway in Breast Cancer Cells by Covalent Modification of p65 Protein.

J Biol Chem 2016 Feb 18;291(7):3639-47. Epub 2015 Dec 18.

From the Departments of Physiology and Biophysics and.

In breast tumors, activation of the nuclear factor κB (NFκB) pathway promotes survival, migration, invasion, angiogenesis, stem cell-like properties, and resistance to therapy--all phenotypes of aggressive disease where therapy options remain limited. Adding an anti-inflammatory/anti-NFκB agent to breast cancer treatment would be beneficial, but no such drug is approved as either a monotherapy or adjuvant therapy. To address this need, we examined whether dimethyl fumarate (DMF), an anti-inflammatory drug already in clinical use for multiple sclerosis, can inhibit the NFκB pathway. We found that DMF effectively blocks NFκB activity in multiple breast cancer cell lines and abrogates NFκB-dependent mammosphere formation, indicating that DMF has anti-cancer stem cell properties. In addition, DMF inhibits cell proliferation and significantly impairs xenograft tumor growth. Mechanistically, DMF prevents p65 nuclear translocation and attenuates its DNA binding activity but has no effect on upstream proteins in the NFκB pathway. Dimethyl succinate, the inactive analog of DMF that lacks the electrophilic double bond of fumarate, is unable to inhibit NFκB activity. Also, the cell-permeable thiol N-acetyl l-cysteine, reverses DMF inhibition of the NFκB pathway, supporting the notion that the electrophile, DMF, acts via covalent modification. To determine whether DMF interacts directly with p65, we synthesized and used a novel chemical probe of DMF by incorporating an alkyne functionality and found that DMF covalently modifies p65, with cysteine 38 being essential for the activity of DMF. These results establish DMF as an NFκB inhibitor with anti-tumor activity that may add therapeutic value in the treatment of aggressive breast cancers.
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http://dx.doi.org/10.1074/jbc.M115.679704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4751401PMC
February 2016

NFκB affects estrogen receptor expression and activity in breast cancer through multiple mechanisms.

Mol Cell Endocrinol 2015 Dec 18;418 Pt 3:235-9. Epub 2014 Oct 18.

Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL 60612, USA.

Estrogen receptor (ER) and NFκB are two widely expressed, pleiotropic transcription factors that have been shown to interact and affect one another's activity. While the ability of ER to repress NFκB activity has been extensively studied and is thought to underlie the anti-inflammatory activity of estrogens, how NFκB signaling affects ER activity is less clear. This is a particularly important question in breast cancer since activation of NFκB in ER positive tumors is associated with failure of endocrine and chemotherapies. In this review, we provide an update on the multiple mechanisms by which NFκB can influence ER activity, including down-regulation of ER expression, enhanced ER recruitment to DNA, and increased transcriptional activity of both liganded and unliganded ER. Additionally, a novel example of NFκB potentiation of ER-dependent gene repression is reviewed. Together, these mechanisms can alter response to endocrine therapies and may underlie the poor outcome for women with ER positive tumors that have active NFκB signaling.
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http://dx.doi.org/10.1016/j.mce.2014.09.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4402093PMC
December 2015

Growth hormone potentiates 17β-estradiol-dependent breast cancer cell proliferation independently of IGF-I receptor signaling.

Endocrinology 2013 Sep 19;154(9):3219-27. Epub 2013 Jun 19.

Department of Physiology and Biophysics, University of Illinois at Chicago, 835 South Wolcott Avenue, MC 901, Chicago, Illinois 60612, USA.

Estrogen action in mammary gland development and breast cancer progression is tightly linked to the GH/IGF-I axis. Although many of the effects of GH on mammary gland growth and development require IGF-I, the extent to which GH action in breast cancer depends on IGF-I is not known. We examined GH action in a panel of estrogen receptor-positive breast cancer cell lines and found that T47D cells express significant levels of GH receptor and that GH significantly enhances 17β-estradiol (E2)-stimulated proliferation in these cells. GH action in the T47D cells was independent of changes in IGF-I and IGF-I receptor (IGF-IR) expression and IGF-IR signaling, suggesting that GH can exert direct effects on breast cancer cells. Although E2-dependent proliferation required IGF-IR signaling, the combination of GH+E2 overcame inhibition of IGF-IR activity to restore proliferation. In contrast, GH required both Janus kinase 2 and epidermal growth factor receptor signaling for subsequent ERK activation and potentiation of E2-dependent proliferation. Downstream of these pathways, we identified a number of immediate early-response genes associated with proliferation that are rapidly and robustly up-regulated by GH. These findings demonstrate that GH can have important effects in breast cancer cells that are distinct from IGF-IR activity, suggesting that novel drugs or improved combination therapies targeting estrogen receptor and the GH/IGF axis may be beneficial for breast cancer patients.
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http://dx.doi.org/10.1210/en.2012-2208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3749474PMC
September 2013

Cisplatin induced damage in kidney genomic DNA and nephrotoxicity in male rats: the protective effect of grape seed proanthocyanidin extract.

Food Chem Toxicol 2009 Jul 5;47(7):1499-506. Epub 2009 Apr 5.

Department of Biotechnology, Institute of Graduate Studies and Research, Alexandria University, Alexandria, Egypt.

The clinical use of cisplatin is highly limited, because of its renal toxicity. In this study, the protective effect of grape seed proanthocyanidin extract (GSPE) against cisplatin-induced nephrotoxicity is investigated in rats. Results showed that DNA qualitative analysis indicated an increase in the instability of the DNA purified from the cisplatin exposed kidney cells. Agarose gel electrophoresis revealed DNA damage in the form of smearing as well as ladder like fragmentation of the kidney genomic DNA. Cisplatin produced different RAPD patterns compared to control. Deletion of bands for the amplified DNA extracted from cisplatin treated rats was the most common outcome. Treatment with cisplatin decreased albumin, and increased urea and creatinine. Cisplatin significantly increased the level of kidney free radicals, and decreased the glutathione content and the activities of the antioxidant enzymes. The presence of GSPE with cisplatin significantly alleviated its nephrotoxicity. In conclusion, the present study showed that cisplatin induced damage in the kidney genomic DNA, lipid peroxidation, inhibition of antioxidant enzymes and alterations of biochemical parameters in plasma and kidney of rats. While, GSPE treatment protected against the toxic effects induced by cisplatin. Thus, GSPE may be used to prevent toxicity during chemotherapeutic treatment with cisplatin.
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http://dx.doi.org/10.1016/j.fct.2009.03.043DOI Listing
July 2009
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