Triple Negative Breast Cancer (TNBC) is one of the most aggressive and hot BC subtypes. Our research group has recently shed the light onto the utility of natural compounds as effective immunotherapeutic agents. The aim of this study is to investigate the role of a methoxylated quercitin glycoside (MQG) isolated from Cleome droserifolia in harnessing TNBC progression and tuning the tumor microenvironment and natural killer cells cytotoxicity. Results showed that MQG showed highest potency in repressing cellular proliferation, colony forming ability, migration and invasion capacities.Mechanistically, MQG was found to modulate a circuit of competing endogenous RNAs where it was found to reduce the oncogenic MALAT-1 lncRNA and induced TP53 and its downstream miRNAs; miR-155 and miR-146a. In turn, this lead to alteration in several downstream signaling pathways such as nitric oxide machinery, natural killer cells through inducing the expression of its activating ligands such as MICA/B, ULBP2, CD155 and ICAM-1 and trimming of the immune suppressive cytokines such as TNF-α and IL-10. In conclusion, this study shows that MQG act as a compelling anti-cancer agent repressing TNBC hallmarks, activating immune cell recognition and alleviating the immune suppressive tumor microenvironment experienced by TNBC patients.

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Background: Recently, a novel crosstalk between non-coding RNAs (ncRNAs) has been casted. However, this has been seldomly investigated in metastatic BC (mBC). H19 and miR-486-5p role in mBC is controversial. ICAM-1 is a recently recognized metastatic engine in mBC. Natural compounds were recently found to alter ncRNAs/target circuits. Yet, Hesperitin modulatory role in altering such circuits has never been investigated in mBC. Objective: The aim of this study is to investigate the impact of hesperitin on miR-486-5p/H19/ICAM-1 axis Methodology: BC patients (n=20) were recruited in the study. Bioinformatic analysis was performed using different prediction softwares. MDA-MB-231 and MCF-7 cells were cultured and transfected using several oligonucleotides or treated with serial dilutions of hesperitin. RNA was extracted and gene expression analysis was performed using q-RT-PCR. ICAM-1 protein levels were assessed using human ICAM-1 Elisa Kit. Cytotoxic potential of hesperitin against normal cells was assessed by LDH assay. Several functional analysis experiments were performed such as MTT, colony forming and migration assays. Results: The study showed that miR-486-5p and H19 has a paradoxical expression profiles in mBC patients. miR-486-5p mimics and H19 siRNAs repressed ICAM-1 and halted mBC hallmarks. A novel crosstalk between miR-486-5p and H19 was observed highlighting a bi-directional relationship between them. Hesperetin restored the expression of miR-486-5p, inhibited H19 lncRNA and ICAM-1 expression and selectively regressed mBC cell aggressiveness. Conclusion: miR-486-5p and H19 are inter-connected upstream regulators for ICAM-1 building up miR-486-5p/H19/ICAM-1 axis that has been successfully tuned in mBC cells by hesperitin

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expression of miR-17-5p mimics resulted in a repression of STAT3, H19 and induction of ULBP2 levels. Knocking down of STAT3 repressed H19 levels and induced ULBP2. Consquently, H19 siRNAs induced ULBP2 levels.Conclusions: This study showed miR-17-5p/STAT3/H19 as a vital regulatory axis for ULBP2 in BC cells. The current evidence also supports the nomination of miR-17-5p as a potential therapeutic option for BC patients counteracting the immune intolerance phenomena exhibited by BC cells.Legal entity responsible for the study: German University in Cairo.

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