Abstract
Investigating dietary polyphenolic compounds as antitumor agents are rising due to the growing evidence of the close association between immunity and cancer. Cancer cells elude immune surveillance for enhancing their progression and metastasis utilizing various mechanisms. These mechanisms include the upregulation of programmed death-ligand 1 (PD-L1) expression and Epithelial-to-Mesenchymal Transition (EMT) cell phenotype activation. In addition to its role in stimulating normal embryonic development, EMT has been identified as a critical driver in various aspects of cancer pathology, including carcinogenesis, metastasis, and drug resistance. Furthermore, EMT conversion to another phenotype, Mesenchymal-to-Epithelial Transition (MET), is crucial in developing cancer metastasis. A central mechanism in the upregulation of PD-L1 expression in various cancer types is EMT signaling activation. In breast cancer (BC) cells, the upregulated level of PD-L1 has become a critical target in cancer therapy. Various signal transduction pathways are involved in EMT-mediated PD-L1 checkpoint overexpression. Three main groups are considered potential targets in EMT development; the effectors (E-cadherin and Vimentin), the regulators (Zeb, Twist, and Snail), and the inducers that include members of the transforming growth factor-beta (TGF-β). Meanwhile, the correlation between consuming flavonoid-rich food and the lower risk of cancers has been demonstrated. In BC, polyphenols were found to downregulate PD-L1 expression. This review highlights the effects of polyphenols on the EMT process by inhibiting mesenchymal proteins and upregulating the epithelial phenotype. This multifunctional mechanism could hold promises in the prevention and treating breast cancer.
Highlights
The association between metastasis and immunity is considered a hallmark of cancer [1]
programmed death-ligand 1 (PD-L1) upregulation is closely associated with multidrug resistance protein 1 (MDR1) expression in breast cancer (BC) cells, and it is mediated by the activation of PI3K/AKT and mitogen-activated protein kinase (MAPK) signaling pathways [65]
We summarized the most-studied compounds and highlighted their potential to target PD-L1 in BC cells, either directly or indirectly, through modulating Epithelial-toMesenchymal Transition (EMT) markers-mediating PD-L1 activation. This summary will provide a closer look at the polyphenols’ most specific studies that could be used combined with the current use of PD-L1 blockade and anti-PD-1 immunotherapy to enhance their efficacy against BC
Summary
The association between metastasis and immunity is considered a hallmark of cancer [1]. The opposite was found in its counterpart, which arises from mesenchymal carcinoma cell models that demonstrating high levels of PD-L1 [22] It was known from previous studies using BC cell lines that polyphenols have the potential to impair BC metastasis through numerous mechanisms such as activating the tissue inhibitors of metalloproteinases (TIMPs) expression while inhibiting the matrix metalloproteinase (MMPs) expression [23,24,25], interfering with various signaling pathways, including phosphoinositide 3-kinases/protein kinase B/mammalian target of rapamycin (PI3Ks/AKT/mTOR) [26,27], mitogen-activated protein kinase (MAPK) [28,29], Vascular endothelial growth factor (VEGF) [30], nuclear factor kappa light chain enhancer of activated B cells (NF-κB) [31,32,33] pathways, and modulating EMT process.
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