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Review
. 2021 Apr 7;13(4):1212.
doi: 10.3390/nu13041212.

The Anticancer Effects of Flavonoids through miRNAs Modulations in Triple-Negative Breast Cancer

Getinet M Adinew  1 , Equar Taka  1 , Patricia Mendonca  1 , Samia S Messeha  1 , Karam F A Soliman  1
Affiliations
Review

The Anticancer Effects of Flavonoids through miRNAs Modulations in Triple-Negative Breast Cancer

Getinet M Adinew et al. Nutrients. .

Abstract

Triple- negative breast cancer (TNBC) incidence rate has regularly risen over the last decades and is expected to increase in the future. Finding novel treatment options with minimum or no toxicity is of great importance in treating or preventing TNBC. Flavonoids are new attractive molecules that might fulfill this promising therapeutic option. Flavonoids have shown many biological activities, including antioxidant, anti-inflammatory, and anticancer effects. In addition to their anticancer effects by arresting the cell cycle, inducing apoptosis, and suppressing cancer cell proliferation, flavonoids can modulate non-coding microRNAs (miRNAs) function. Several preclinical and epidemiological studies indicate the possible therapeutic potential of these compounds. Flavonoids display a unique ability to change miRNAs' levels via different mechanisms, either by suppressing oncogenic miRNAs or activating oncosuppressor miRNAs or affecting transcriptional, epigenetic miRNA processing in TNBC. Flavonoids are not only involved in the regulation of miRNA-mediated cancer initiation, growth, proliferation, differentiation, invasion, metastasis, and epithelial-to-mesenchymal transition (EMT), but also control miRNAs-mediated biological processes that significantly impact TNBC, such as cell cycle, immune system, mitochondrial dysregulation, modulating signaling pathways, inflammation, and angiogenesis. In this review, we highlighted the role of miRNAs in TNBC cancer progression and the effect of flavonoids on miRNA regulation, emphasizing their anticipated role in the prevention and treatment of TNBC.

Keywords: cancer; flavonoid; microRNA; triple-negative breast cancer.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Upregulation and downregulation of specific miRNAs could result in TNBC cell differentiation, cell proliferation, induction of malignant effects, and reduction of apoptosis. Upregulated oncogenic miRNAs enhance EMT and metastasis, induce proliferation, invasion, migration, increase cancer cells’ stemness, and reduce apoptosis [68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103]. Oncosuppressor miRNAs were downregulated and are associated with chemoresistance, tumor proliferation, poor survival rates, distal metastasis, poor prognosis, promoting EMT, invasion, migration, and reducing apoptosis. On the contrary, overexpression of these miRNAs represses EMT, suppresses cell growth, proliferation, migration, invasion, tumor cell motility, and promotes apoptosis in TNBC [92,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152]. TNBC—Triple negative breast cancer, EM—epithelial-to-mesenchymal transition.
Figure 2
Figure 2
Alteration of miRNAs expression is associated with stemness, EMT, proliferation, metastasis, and apoptosis through targeting several endogenous molecules that contribute to the carcinogenesis of TNBC. PTEN—phosphate and tensin homology, TRPS1—trichorhinophalangeal 1, ADIPOR1—adiponectin receptor 1, CCAAT—enhancer binding protein beta (C/EBPβ), FN1—fibronectin 1, MSN—moesin, NTRK2 or TrkB—neurotrophic tyrosine receptor kinase type 2, LEPR—leptin receptor, ARHGAP19—Rho GTPase activating protein 19, BCSC—breast cancer stem cell, ATM—Ataxia telangiectasia mutated, FOXP2—factor Forkhead-box P2, HMGA2—high-mobility group A protein 2, BT-ICs—breast tumor-initiating cells, Ubc9—ubiquitin-conjugating enzyme 9, ITGB3 (integrin beta3, CSC—cancer stem cell, IGFII—insulin-like growth factor II (mRNA binding protein (IMP3), SETDB1—SET domain bifurcated 1, PFN1—profilin 1, LIFR—leukemia inhibitory factor receptor, EI24—etoposide induced 2.4, APC—adenomatous polyposis coli, XIAP—X linked inhibitor of apoptosis, UBASH3B—ubiquitin-associated and SH3 domain-containing B, v-myc—myelocytomatosis viral oncogene homolog (c-Myc), ZEB1—zinc finger E-box binding homeobox 1, ARF—ARF proteins, MUC1—Mucin1, CORO1C—Coronin 1C, RoR—regulator of reprogramming, ROR1—RTK-like orphan receptor 1, RGS3—G protein signaling 3, BTG2—B-cell translocation gene 2, RUNX3—runt-related transcription factor 3, BIRC5—baculoviral IAP repeat-containing protein 5, LASP1—Lim and SH3 domain protein 1, EZH2—enhancer of Zeste homolog 2, MTDH—Metadherin, AEG-1—astrocyte elevated gene 1, TNKS2—tankyrase 2, LIMK1—LIM kinase-1, LIMK2—LIM kinase-2, ETV1- ETS variant 1, LAMA4—laminin subunit alpha 4, KLF5—Krüppel-like factor 5, MTA2—metastasis-associated protein 2, RIP1—receptor-interacting protein 1, CYLD—cylindromatosis, DR4/5death receptor 4/5, SOCS1—cytokine signaling 1, cIAP1—cellular inhibitor of apoptosis.
Figure 3
Figure 3
TNBC miRNA therapeutic strategy. Inhibiting the function of OncomiR by the use of miRNAs suppression and promoting the activity of tumor suppressor miRNAs through miRNA mimics can serve as novel therapeutic options against TNBC.
Figure 4
Figure 4
Basic chemical structure of flavonoid. Three rings are normally considered and labeled with letters A, B, and C. The oxygen atom is numbered as the first position in the heterocyclic ring labeled as C. The remaining carbon atoms are numbered from C2 to C10. Ring B shows six positions from C1′ to C6′.
Figure 5
Figure 5
Classification of flavonoids. Based on the degree of oxidation of the central pyran ring flavan, flavonoids are classified into six groups: flavonols, flavanones, isoflavones, flavan-3-ols, flavones, and anthocyanidins. Some common examples are listed under each group.
Figure 6
Figure 6
Common dietary sources of flavonoids. Flavonoids are ubiquitously found in edible plants, fruits, and vegetables.
Figure 7
Figure 7
Proposed mechanism of action of flavonoids in the prevention and therapy of TNBC. The anticancer activity of flavonoids is associated with their modulation of signal transduction pathways and inhibition of angiogenesis, proliferation, and metastasis, while promoting apoptosis.
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