A Review of Natural Therapies Potentially Relevant in Triple Negative Breast Cancer Aimed at Targeting Cancer Cell Vulnerabilities

Abstract

We reviewed the research into the mechanisms of growth of triple negative breast cancer (TNBC) based on laboratory pre-clinical studies that have shaped understanding of the disease over the past decade. In response to these findings, we propose an approach to potentially prevent cancer metabolic adaptation and recurrence. This paper collates pre-clinical results, first to determine the tumor’s mechanisms of growth and then to source natural substances that could potentially suppress those mechanisms. The results from in vivo and in vitro studies of TNBC were combined first to select 10 primary mechanisms (Hypoxia-inducible factor 1α, Hedgehog, MAPK, MTAP, NF-κ B, Notch, P13K, STAT3, and Wnt signaling pathways plus p53 and POL2A gene expression) that promote TNBC growth, and second to propose a treatment array of 21 natural compounds that suppress laboratory models of TNBC via these mechanisms. We included BRCA mutations in the review process, but only pathways with the most preclinical studies utilizing natural products were included. Then we outlined potential biomarkers to assess the changes in the micro-environment and monitor biochemical pathway suppression. This suppression-centric aim targets these mechanisms of growth with the goal of potentially halting tumor growth and preventing cancer cell metabolic adaptation. We chose TNBC to demonstrate this 5-step strategy of supplementary therapy, which may be replicated for other tumor types.

Prioritization of cancer driver gene with prize-collecting steiner tree by introducing an edge weighted strategy in the personalized gene interaction network

“…14 , we can see that most significant pathway among top 20 ranking pathways for BLCA, BRCA, COAD and HNSC is “pathways in cancer”, demonstrating that the predicted driver genes with our PDGPCS are significantly related with cancers. We also identified other cancer-related pathways for BLCA, BRCA, COAD and HNSC, such as “PI3K-Akt signaling pathway” [ 23 ] and “ErbB signaling pathway” [ 24 ] for BLCA, “MAPK signaling pathway” [ 25 ] and “Jak-STAT signaling pathway” [ 26 ] for BRCA, “Rap1 signaling pathway” [ 27 ] for COAD, and “VEGF signaling pathway” for HNSC [ 28 ].

Fig.

…”

Anticancer activity of Piper cubeba L. extract on triple negative breast cancer MDA-MB-231

“…There are many compounds of plants (such as Allium spp., Glycine spp., Curcuma longa and Panax ginseng) that can inhibit triple negative breast cancer through the specific pathway including HIF-I, MAPK, MTAP, NF-B, PI3K, p53 and STAT3. The inhibition of these pathways causes inhibition of tumor growth and induction of apoptosis (Webb and Kukard, 2020).…”

Compounds from diverse natural origin against triple‐negative breast cancer: A comprehensive review

“…Tumor cells can adapt and change their mechanism of action to use biochemical pathways that are unaffected by usual pharmaceutical therapies. While chemotherapy is one of the most effective cancer therapies, some tumor cells are resistant to this treatment (Webb & Kukard, 2020). Breast cancer (BC) is the second most usually diagnosed cancer type and the second most common cause of cancer death, up to 15% of women in the United States, after lung cancer.…”

“…Chemotherapy and radiotherapy are the typically used treatment for TNBC, but it has been found that these cells are resistant to these treatments. The overall survival with TNBC is lower than in other types of BC (Knickle et al, 2018; Webb & Kukard, 2020). The comparison of receptors between normal breast cancer cells and TNBC cells (Damaskos et al, 2021) is given in Figure 1.…”

“…Tumorigenesis in TNBC is caused by mutation or overexpression of tumor suppressor genes (Webb & Kukard, 2020), which are proteins that control cell division and replication as well as prevent cancer cell development (Macleod, 2000). They play two major roles: (i) gatekeepers and (ii) caretakers.…”