Overcoming the Challenges of Phytochemicals in Triple Negative Breast Cancer Therapy: The Path Forward

Abstract

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 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. More research is required to better understand the role of phytochemicals in TNBC therapy, or to advance the development of more effective delivery mechanisms for these phytochemicals to the site where they are required. This review will discuss the promise shown by phytochemicals as a treatment option for TNBC.

Keywords: Wnt; angiogenesis; apoptosis; epithelial to mesenchymal transition; metastasis; phytomedicine; tyrosine kinase.

Figure 4

Structure of phytochemicals discussed in this review.

Figure 1

Tyrosine kinase (EGF pathway) and Wnt/β-catenin pathways. The separate pathways that control cell proliferation, cell survival, metastasis, angiogenesis, and inflammation that can be targeted by phytochemicals. The Wnt signaling pathway controls the activation of the Notch signaling pathway and controls the expression of the VEGF pro-angiogenic growth factor. The EGF and other receptor tyrosine kinase signaling activates Cox pathways, which promote inflammation through the production of prostaglandins. This results in the activation of the AKT protein, leading to pro-survival factors, inhibiting apoptosis. Finally, the ERK and MAPK pathways lead to the activation of cell migration, induction of cell proliferation, and angiogenesis.

Figure 2

Overlap between the tyrosine kinase pathway, Wnt/β-catenin, and prostaglandin inflammation pathways. The first point of overlap is the Cox protein, which is activated through receptor tyrosine kinase signaling, then the resulting prostaglandins, which activate the EP4 transmembrane receptor, which in turn can activate the AKT pathway leading to the transactivation of the PPARδ transcription factor. The expression of PPARδ is activated by the Wnt signaling pathway. This transcription factor promotes survival by inhibiting apoptosis.

Figure 3

The EMT transition pathway. The initiation of endothelial to mesenchymal transition is required for the spread and invasion of cancer as well as angiogenesis, which is required for the growth of tumors. The EMT pathway can be activated by multiple receptor tyrosine kinases as well as through Wnt, integrin, and inflammation signals. The end result is the activation of what is known as EMT transcription factors (TFs), which lead to the transcription and expression of a multitude of genes that are involved in the EMT process.

Figure 5

A summary of the targeting of cancer pathways by phytochemicals. Multiple phytochemicals isolated from multiple different species and families of plants act on what are termed the hallmarks of cancer. These are the processes that define the transition from normal cells to cancer cells. Despite these compounds being derived from a wide range of plants, they target very common pathways. These include immune evasion, angiogenesis, metastasis, proliferation, and the inhibition of cell death.