*Review* **Countering Triple Negative Breast Cancer via Impeding Wnt/**β**-Catenin Signaling, a Phytotherapeutic Approach**

**Laleh Arzi 1,\* , Homa Mollaei <sup>2</sup> and Reyhane Hoshyar <sup>3</sup>**


**\*** Correspondence: laleh.arzi@ut.ac.ir; Tel.: +98-9122574325

**Abstract:** Triple negative breast cancer (TNBC) is characterized as a heterogeneous disease with severe malignancy and high mortality. Aberrant Wnt/β-catenin signaling is responsible for selfrenewal and mammosphere generation, metastasis and resistance to apoptosis and chemotherapy in TNBC. Nonetheless, in the absence of a targeted therapy, chemotherapy is regarded as the exclusive treatment strategy for the treatment of TNBC. This review aims to provide an unprecedented overview of the plants and herbal derivatives which repress the progression of TNBC through prohibiting the Wnt/β-catenin pathway. Herbal medicine extracts and bioactive compounds (alkaloids, retinoids. flavonoids, terpenes, carotenoids and lignans) alone, in combination with each other and/or with chemotherapy agents could interrupt the various steps of Wnt/β-catenin signaling, i.e., WNT, FZD, LRP, GSK3β, Dsh, APC, β-catenin and TCF/LEF. These phytotherapy agents diminish proliferation, metastasis, breast cancer stem cell self-renewal and induce apoptosis in cell and animal models of TNBC through the down-expression of the downstream target genes of Wnt signaling. Some of the herbal derivatives simultaneously impede Wnt/β-catenin signaling and other overactive pathways in triple negative breast cancer, including: mTORC1; ER stress and SATB1 signaling. The herbal remedies and their bioactive ingredients perform essential roles in the treatment of the very fatal TNBC via repression of Wnt/β-catenin signaling.

**Keywords:** herbal medicine; bioactive derivative; triple negative breast cancer; Wnt/β-catenin; anti-cancer

### **1. Introduction**

Breast cancer was reported as the most diagnosed cancer and the leading cause of cancer mortality worldwide among women in 2020 [1]. Advances in molecular techniques have prompted a conventional classification of breast cancer. The St. Gallen International Breast Cancer Conference 2011 allocated four molecular subtypes to breast cancers: Luminal A (ER+/PR+/HER2-/lowKi-67); Luminal B (ER+/PR+/HER2-/+/high Ki-67); HER2-overexpression (ER-/PR-/HER2+) and triple negative breast cancers (TNBCs) (ER-/PR-/HER2-) [2]. The TNBC is characterized as the most aggressive and fatal subtype, particularly in young women. It is famed as "the kiss of death", being attributed with a poor chance of survival, early relapse, high proliferation and metastatic potential, heterogeneity and lack of efficient, approved targeted therapies [3–5]. Molecular analysis has evidenced that various signaling pathways are activated in the TNBC cells, such as Wnt/βcatenin, Hedgehog, Notch, TNF-α, Hippo and JAK-STAT [6]. However, since aberrant the Wnt/β-catenin pathway was reported as a predisposing factor of TNBC, prohibition of this pathway could be a worthwhile target for conquering TNBC progress [7–9]. The Wnt-signaling pathway is associated with cell proliferation, survival, invasion, metastasis and chemotherapy resistance in TNBC [10].

**Citation:** Arzi, L.; Mollaei, H.; Hoshyar, R. Countering Triple Negative Breast Cancer via Impeding Wnt/β-Catenin Signaling, a Phytotherapeutic Approach. *Plants* **2022**, *11*, 2191. https://doi.org/ 10.3390/plants11172191

Academic Editors: Juei-Tang Cheng, I-Min Liu and Szu-Chuan Shen

Received: 19 July 2022 Accepted: 21 August 2022 Published: 24 August 2022

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**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

<sup>1</sup> Department of Microbiology, Shahr-e-Qods Branch, Islamic Azad University, Tehran 37515-374, Iran

The Wnt signaling commences with the binding of Wnt ligands to the N-terminal extra-cellular cysteine-rich domain of the Frizzled (FZD) seven-pass transmembrane receptors and the LDL receptor-related proteins (LRP coreceptor). The trimetric complex (Wnt, FZD and LPR) recruits phosphorylated Disheveled (Dsh) and Axin, to prevent β-catenin phosphorylation. Therefore the APC/CK1/GSK-3β/Axin/β-catenin degradation complex is inactivated and the phosphorylation of β-catenin by GSK-3β is repressed. The accumulated β-catenin in the cytoplasm translocates into the nucleus, where it modulates the target gene expression with the T cell factor/lymphoid enhancer factor (Tcf/Lef) family of transcription factor [11]. Besides the classical canonical β-catenin-dependent mechanism of Wnt signaling, this pathway might progress through alternative signaling called "β-catenin independent mechanisms or non-canonical pathways" [12].

Although chemotherapeutic agents have been employed as exclusive treatments of TNBC, the resistance to chemotherapy agents (anthracyclines, taxanes, capecitabine, gemcitabine, eribulin), biomarker-based treatments and checkpoint-based immunotherapy has led to inconsequential responses to the medications. An extensive spectrum of clinical investigations has claimed the favorable influence of herbal remedies on the survival, immune enhancement and quality of life of cancer sufferers [13]. Moreover, due to their pharmacological safety, these compounds can be applied alone or complementary to chemotherapy in order to boost the therapeutic efficacy and diminish the chemotherapyinduced toxicity [14,15]. A myriad of investigations have verified the effectiveness of medicinal plant extracts and their bioactive components in targeting the Wnt pathway as novel therapeutic agents [16–18]. Accordingly, this paper is dedicated to the review and appraisal of plants and natural derivatives which suppress the progression of TNBC through prohibiting the Wnt/β-catenin pathway.
