Breaking Barriers; Phytoestrogens in the Fight Against Triple‐Negative Breast Cancer: A Comprehensive Review

ABSTRACT The development of standard drugs for some unusual cancers, including estrogen‐nonresponsive breast cancer, is somewhat difficult within a very short time. So, considering the current situation, phytoestrogen may be a potential candidate for unraveling chemotherapeutics agents. The reason for this review article is to manifest overall information regarding the effects of phytoestrogen on triple‐negative breast cancer (TNBC), along with its related cellular and molecular pathways in different TNBC models. Data was retrieved by systematic searches according to PRISMA guidelines, and commonly used tools and servers are BioRender, ChemDraw professional 16.0, Schrodinger, and ADMETlab 2.0. TNBC may be caused due to dysregulation of several signaling mechanisms such as Wnt/β‐catenin, hedgehog, MAPK, notch, PI3K/AKT/mTOR, hippo, NF‐κB, and JAK/STAT signaling cascades. Among all phytoestrogens ( n = 150), 48 compounds are therapeutically effective on TNBC in some in vitro and preclinical models. Chemotherapeutics activities are regulated through varieties of mechanisms, including targeting signaling pathways such as phosphor‐Akt, PI3K/AKT/mTOR, NF‐κB, TNF‐α; apoptosis such as FASL, Bcl2, Bax, Bak, Bad, apfa1, ASK1, Capase, and PARP; metastasis such as MMPs (1,2,3,9), Wnt/‐β catenin, angiogenesis (E&N Cadherin, Vimentin), cell proliferation (cyclins‐A, B1, D1, E1, and CDKs 1, 6,7), inflammatory molecules (TNF‐α, NF‐κB, IL‐1β, IL‐8), regulating tumor suppressor genes (p21, p27, p51, p53) and some nonspecific pathways like DNA damage and repair (γH2AX, RAD51, and surviving), autophagy (mTOR, ULK1, and cathepsin B), epigenetic (HDAC1, DNMT1, telomerase production) and metabolism regulation (glucose regulation‐GLUT1 and GLUT4), showing antioxidant and many other pathways. Some selective phytoestrogens exert synergistic activities with conventional cancer drugs as well radiotherapy like as conventional mechanism and reverse drug resistance through regulation of the EMT process, signaling pathways, drug sensitizing, miRNA regulation, and improving drug uptake. Nano‐based phytoestrogen can target TNBC cells, stimulate drug accumulation, and improve drug efficacies, making phytoestrogens more effective agents in treating TNBC. Additionally, an in‐silico pharmacokinetics study reveals that phytoestrogen possesses suitable pharmacokinetic characteristics with minor toxicity. So, phytoestrogen can be a potential candidate drug against TNBC until standard and fully effective pharma drugs are available at markets.