Flavonoids Modulations in TNBC: History
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Subjects: Nutrition & Dietetics
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GETINET ADINEW

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. 

  • cancer
  • flavonoid
  • microRNA
  • triple-negative breast cancer

1. Introduction

Globally, breast cancer (BC) is the major and most common repeatedly diagnosed cancer in women, which accounts for 30% of new female cancer cases [1], and also the second cause of death in women worldwide [2]. Approximately 1 million breast cancer cases are diagnosed annually worldwide [3]. In the United States, more than 276,000 new breast cancer cases were estimated by the end of 2020, and 12.9% of all women will be diagnosed with breast cancer over their lifetime [4][5][6][7]. Approximately 15% of breast cancers are categorized as triple- negative breast cancer (TNBC), characterized by a poor prognosis, early relapse, distant recurrence, unresponsiveness to conventional treatment, aggressive tumor growth, aggressive clinical demonstration, and lowest survival rate [8]. Compared with other BC subtypes, TNBC is more often associated with hereditary conditions. Evidence showed that among newly diagnosed BC patients, around 35% of BC suppressor protein1 (BRCA1) and 8% of BC suppressor protein2 (BRCA2) mutations in this population were TNBC [9]. Lack of progesterone (PR), estrogen (ER), and human epidermal growth factor receptor 2 (HER2) receptors are the major features of TNBC [10]. Recently, according to intrinsic gene signature, TNBC can be classified into six main types: basal-like 1 and 2, mesenchymal stem-like, immunomodulatory, mesenchymal, and luminal androgen receptor [11]. Of the TNBC cases, an estimated 75% are basal-like [12]. The prevalence of TNBC in African American women is higher than non-African American women. Indeed, 39% of African American premenopausal women diagnosed with BC are TNBC [13]. Previously reported studies revealed the continuous increase in BC incidence rate over the last decades and in the future [14].

Chemotherapy and radiotherapy are the two most common treatment strategies for TNBC patients in the early or advanced stages [15]. Compared to hormone receptor-positive patients, TNBC patients initially respond to conventional chemotherapy. However, the frequent disease relapse results in the worst outcome and low survival rate due to high metastasis rates and lack of effective treatment after relapse [16][17]. Although chemoresistance is a challenge that accounts for a significant share of drug failures [18], chemotherapy remains the primary cancer treatment approach. It is the only agent approved by the Food and Drug Administration (FDA) in treating nonmetastatic TNBC [19]. Even though the mechanism of resistance depends on the chemotherapeutic agent and patient; drug inactivation, drug target alteration, DNA damage repair, cell death inhibition, cancer cell heterogeneity, epigenetic alteration, and epithelial–mesenchymal transition or combination of these are the major direct or indirect contributing factor for developing resistance against cancer chemotherapeutic agents [18]. In TNBC cells, epigenetic mechanisms are implicated in chemotherapy resistance. For instance, an inherent defect in drug uptake and a lack of reduced folate carrier expression is the main cause of methotrexate resistance in MDA-MB-231 cells. However, treating MDA-MB-231 cells with DNA methylation inhibitor or reduced folate carrier cDNA was previously reported to restore methotrexate uptake and enhance sensitivity to methotrexate [20].

MicroRNAs were identified to be correlated with chemoresistance in TNBC. For instance, resistance to neoadjuvant chemotherapy was strongly linked to upregulated miR-181a [21]. Similarly, in the MDA-MB-231 cell line, upregulation of miR-21-3p, miR-155-5p, miR-181a-5p, miR-181b-5p, 183-5p and downregulation of miR-10b-5p, miR-31-5p, miR-125b-5p, miR-195-5p, and miR-451a were associated with doxorubicin resistance [22][23]. Moreover, downregulation of miR-200c was associated with doxorubicin resistance, poor response to radiotherapy, and increased multidrug resistance mediated gene expression [24]. Taken all together, chemoresistance is still a challenge in preventing and treating TNBC, and finding the best options is needed to manage the disease by developing drugs that combat the resistance gene or any target molecules of TNBC, miRNAs.

2. Flavonoids in the Prevention and Therapy of TNBC

Anticancer drugs for treating TNBC patients are currently limited since this type of BC lacks the expression of hormone receptors and HER2 amplification [25][26]. Hence, extensive research is directed to the disease’s molecular features, seeking naturally found agents with potential in preventing and treating cancers, including TNBC. Plants (fruits, vegetables, herbs), animals, and microbes, including natural products and secondary metabolites, are sources of many bioactive compounds that have been innovated into drugs to treat disease. Currently, more than 60% of anticancer drugs are obtained from natural products [27]. Active ingredients such as flavonoids, alkaloids, polysaccharides, terpenoids, and saponins derived from natural products have potent anticancer, analgesia, immunomodulation, antioxidant, anti-inflammatory, ant-viral, and antibacterial activities. Since chemoresistance is becoming more frequent and a challenge in treating cancer patients, including TNBC, discovering novel anticancer drugs from natural sources is a priority. Studies have shown that flavonoids have been used in managing TNBC [28]. Moreover, flavonoids also exhibit a strong potential to enhance the effectiveness of currently used conventional chemotherapeutic drugs and, most importantly, they are cost-effective and environmentally friendly [29].

Tumor metastasis is a common feature of TNBC and the major cause of BC-related mortality. In a previous study on the TNBC cell line MDA-MB-231, authors found that Glabridin, an isoflavone from licorice root, strongly inhibited cell metastasis and invasion and decreased tumor angiogenesis [30]. Myricetin-treated MDA-MB-231 cells showed a significant reduction of cell viability, migration, metastasis, invasion, and adhesion through repressing the protein expression of MMP-2/9 [31]. Similarly, studies reported that exposure of the MDA-MB-231 TNBC cell to epigallocatechin-3-gallate, abundantly found in consumed tea, strongly repressed cell proliferation and invasion, caused G0/G1 cell-cycle arrest, reduced activation of MMP-2/9, suppressed expression of Bcl-2/Bax, decreased expression of c-Met receptor and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kβ) proteins levels, reduced phosphorylation of Akt, and promoted cell death by apoptosis [32]. Furthermore, in vitro studies on breast cancer cases showed that a time-dependent exposure of cells to kaempferol induced G2/M arrest by repressing cyclin A, Cyclin B, and CDK1 as promoted apoptosis by p53 phosphorylation in MDA-MB-231 TNBC cell [33]. Additionally, kaempferol induced caspase-3-dependent apoptotic cell death and reduced tumor growth by inhibiting angiogenic and antiapoptotic gene expressions [34]. Daidzein, one class of isoflavonoid, found in different plants and herbs, has been reported to decrease cell viability, cell migration, and TNBC cell line invasion of MDA-MB-231 cells [35][36][37].

Dysregulation of miRNA is associated with cancer progression and could be an effective target in treating various cancers, including TNBC. Studies have reported that quercetin could modulate oncogenic miRNAs such as Let-7, miR-21, and miR-155, leading to inhibition of cancer initiation, development, proliferation, and apoptosis induction and increased sensitivity of cancer cells to chemotherapy [38]. Furthermore, quercetin inhibits breast cancer cell proliferation and invasion by upregulation of tumor suppressor miR-146a [39]. Likewise, quercetin could modulate the expression of a plethora of miRNAs (48 unique miRNAs). Quercetin strongly repressed tumor metastasis and invasion mediated miRNAs such as miR-146a/b; reduced cell proliferation mediated miRNAs including Let-7 family, and induced apoptosis mediated miRNAs such as miR-605. Quercetin also upregulated tumor suppressor miRNAs such as miR-381 [40]. Exposure of TNBC cells to resveratrol significantly upregulated tumor suppressor miRNAs such as miR-26a in MDA-MB-231 cells [41].

 

This entry is adapted from the peer-reviewed paper 10.3390/nu13041212

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