Triple negative breast cancer (TNBC) is a very aggressive subtype of breast cancer that lacks estrogen, progesterone, and HER2 receptor expression. TNBC is thought to be produced by Wnt, Notch, TGF-beta, and VEGF pathway activation, which leads to cell invasion and metastasis. To address this, the use of phytochemicals as a therapeutic option for TNBC has been researched. Plants contain natural compounds known as phytochemicals. Curcumin, resveratrol, and epigallocatechin-3-O-gallate (EGCG) are phytochemicals that have been found to inhibit the pathways that cause TNBC, but their limited bioavailability and lack of clinical evidence for their use as single therapies pose challenges to the use of these phytochemical therapies.
The molecular mechanisms behind TNBC remain unclear despite the fact that several signaling pathways have been identified as playing a role in the development and progression of TNBC. The epidermal growth factor receptor (EGFR) pathway [37[15][16],38], the PI3K/Akt pathway [39[17][18][19],40,41], the RAS/RAF/MEK/ERK network [42[20][21],43], the Wnt/β-catenin pathway [44[22][23],45], and the cyclooxygenase-2 (COX-2) pathway are among the most well-studied signaling pathways associated with TNBC [46,47][24][25]. These signaling pathways implicated in cancer are known to be targeted by various phytochemicals that show evidence of targeting these molecular pathways, including curcumin, resveratrol, green tea polyphenols, sulforaphane, erucin, genistein, genipin, baicalein, quercetin, isoquercitin, vitamin E, parthenolide, dioscin, triptolide, kaempferol, pterostilbene, isoliquiritigenin, and escin [48][26].
Phytochemicals have recently surfaced as a viable therapy option for TNBC [139][87]. Phytochemicals are plant-derived natural substances that have been demonstrated to have anticancer activities [140][88]. They have gained popularity as potential cancer therapies because of their ability to target many signaling pathways and biological processes that contribute to tumor formation and progression [141][89]. Phytochemicals can fight cancer in a variety of ways, including the induction of apoptosis, the inhibition of angiogenesis, immune system regulation, and cell growth suppression, among others [142][90].
Curcumin, a phytochemical isolated from Curcuma longa, or turmeric, has already been shown to be effective in the treatment of various cancers by inhibiting cell proliferation and inducing apoptosis [143][91]. In the treatment of osteosarcoma, curcumin has been shown to target MAPK/ERK, PI3k/AKT, Wnt/β-catenin, Notch, and microRNA [143][91]. The targeting of the Wnt signaling pathway by curcumin not only inhibits the signaling pathway, but also modifies downstream mediators of the Wnt pathway. These include c-Myc and cyclin D1 [144][92]. Curcumin also has antioxidant, anti-inflammatory, cardio-protective, hepato-protective, and anti-diabetic activities [144][92]. Curcumin interrupts cell proliferation, survival, angiogenesis, and metastasis in TNBC. It is able to act on multiple pathways. These include apoptotic and cell cycle pathways, such as the PI3K/Akt/mTOR pathway, the JAK/STAT pathway, the MAPK pathway, the p53 pathway, and the Wnt/β-catenin pathway [145][93].
The anticancer phytochemical brassinin is derived from cruciferous vegetables and is active against many different types of cancer. When tested against TNBC, this compound reduces the viability of cells and kills endothelial cells before other tumor cells in vitro. Brassinin has negative effects on angiogenesis in TNBC cells, inhibiting proliferation, migration, tube formation, and spheroid sprouting. When it was regularly administered to a dorsal skinfold chamber model of TNBC, it reduced tumor size, microvessel density, and the perfusion of tumor microvessels. The molecular basis of the activities of brassinin include promoting the degradation of Tie2 and fibroblast growth factor receptor 1 [149][94]. Resveratrol, found in red grapes and red wine, is one of the most well-known anticancer compounds [150,151][95][96]. Resveratrol has been found to cause apoptosis, decrease angiogenesis in TNBC cells, and modify the immune system’s response to TNBC tissue and cells [152,153][97][98]. Berberine, is an isoquinoline plant-derived alkaloid, was reported to have anticancer activities, resulting in the creation of synthetic 13-arylalkyl derivatives. Berberine targets the Wnt/β-catenin signaling pathway, inhibiting β-catenin transcriptional activity, and increasing the expression of E-cadherin. Berberine has very low cytotoxicity against normal cells (up to 20 µM). Some of the synthetic compounds based on berberine have higher activity than the natural compound [154][99].