# New Achievements for the Treatment of Triple-Negative Breast Cancer
## 3 Novel Approaches to Therapy in TNBC
### Nutraceuticals in the Prevention and Treatment of TNBC  
Numerous studies have demonstrated that high consumption of fruit and vegetables guarantees a reduced onset of cancer because of the presence of several natural bioactive molecules with anticancer properties [139]. One advantage of natural anticancer compounds is that they are able to selectively interfere with transformed or cancer cells without being toxic to healthy cells. Nutraceuticals, ranging from active phytochemicals, minerals and vitamins all the way to whole functional foods, are extensively studied for the treatment of TNBC [140]. Some recent examples of nutraceuticals used for their antitumor properties are listed with their structures in Table 5.  
One of the most studied nutraceuticals is curcumin, a bioactive component obtained from the rhizome of turmeric (_Curcuma longa_) with a wide spectrum of pharmacological properties [141]. It has been shown to inhibit tridocarban cytotoxicity in BC cells [142] Indeed, human breast cell carcinogenesis may also be induced by endocrine disruptors, such as tridocarban, an antimicrobial agent widely used in soaps, deodorants, shampoos, toothpastes and cosmetics [143; 144]. Moreover, [PERSON] et al. (2016) [145] showed that exposure of MDA-MB-231 cells to curcumin reduced Akt protein expression in a dose- and time-dependent manner, together with activation of autophagy and suppression of ubiquitin-proteasome system (UPS) function. Generally, cell lines derived from aggressive tumor subtypes, such as TNBC, express low levels of vitamin D receptor (VDR) and are less sensitive to 1\(\alpha\),25-dihydroxy vitamin D\({}_{3}\) (1,25D) than those derived from more-differentiated tumor types. The hyaluronic acid synthase 2 (HAS2) gene is overexpressed in a high percentage of breast tumors, especially in basal-like TNBC. It has been reported that 1,25D inhibits HAS2 expression and hyaluronic acid (HA) synthesis in murine TNBC cells. Recently, it was demonstrated that Hs578T cells retain VDR and sensitivity to 1,25D, and that 1,25D suppresses proliferation, HAS2 gene expression and HA production in cells selected for high HA production [146]. The antitumor properties of vitamin D have been recently reviewed [147]. Piperine, a major bioactive constituent of black pepper (_Piper nigrum_) [148], has shown activity against TNBC cells. Particularly, piperie decreased the percentage of TNBC cells in the G2 phase, decreasing G1- and G2-associated protein expression and increasing p21(Waf1/Cip1) expression. Piperine also inhibited survival-promoting Akt activation in TNBC cells and induced the caspase-dependent mitochondrial apoptosis pathway [149]. Luteolin is a natural flavonoid found in citrus fruits, leafy greens, cruciferous vegetables and spices that is very effective against TNBC [150]. Literature data demonstrated that luteolin suppressed in vivo metastasis of human MDA-MB-435 and MDA-MB-231 (4175) LM2 TNBC cells to the lungs. It also inhibited in vitro cell migration and the viability of MDA-MB-435 and MDA-MB-231 (4175) LM2 cells, inducing apoptosis [151]. In addition, [PERSON] et al. (2017) [152] reported that luteolin effectively suppressed metastases of TNBC by reversing epithelial-mesenchymal transition (EMT), which may be mediated by downregulation of \(\beta\)-catenin, in vitro and in vivo. It has been known for many years that resveratrol (RSV), whose major dietary sources include grapes, wine, peanuts and soy, possesses anticancer properties against several types, including BC [153, 154]. Recent studies confirmed the potential use of RSV for the treatment of TNBC. For instance, [PERSON] et al. [155] revealed that RSV may induce TNBC cell apoptosis by decreasing the expression of the DNA polymerase delta catalytic subunit (POLDI), implicated in the activation of the apoptotic pathway. Furthermore, RSV treatment decreased the anti-apoptotic markers of MDA-MB-231 cells, such as proliferating cell nuclear antigen (PCNA) and BCL-2, and increased apoptosis markers, such as caspase-3.