Zinc Favors Triple-Negative Breast Cancer’s Microenvironment Modulation and Cell Plasticity

Abstract

Triple-negative breast cancer (TNBC) tends to metastasize to the brain, a step that worsens the patient’s prognosis. The specific hallmarks that determine successful metastasis are motility and invasion, microenvironment modulation, plasticity, and colonization. Zinc, an essential trace element, has been shown to be involved in all of these processes. In this work, we focus our attention on the potential role of zinc during TNBC metastasis. We used MDA-MB-BrM2 (BrM2) cells, a brain metastasis model derived from the parental TNBC cell line MDA-MB-231. Our studies show that BrM2 cells had double the zinc content of MDA-MB-231 cells. Moreover, exploring different metastatic hallmarks, we found that the zinc concentration is especially important in the microenvironment modulation of brain metastatic cells, enhancing the expression of SerpinB2. Furthermore, we show that zinc promotes the tumorigenic capacity of breast cancer stem cells. In addition, by causing a disturbance in MDA-MB-231 zinc homeostasis by overexpressing the Zip4 transporter, we were able to increase tumorigenicity. Nevertheless, this strategy did not completely recapitulate the BrM2 metastatic phenotype. Altogether, our work suggests that zinc plays an important role in the transformative steps that tumoral cells take to acquire tumorigenic potential and niche specificity.

LOXL1 and LOXL4 are novel target genes of the Zn2+-bound form of ZEB1 and play a crucial role in the acceleration of invasive events in triple-negative breast cancer cells

“…This event is attributed to the enriched Zn-finger motifs in the ZEB1 protein composition (14), but it has not been fully elucidated how Zn 2+ -binding influences the pleiotropic role of ZEB1 through cancer progression. Based on our experience and an extensive PubMed search, most of the published studies on ZEB1 involved experiments exploiting Zn 2+ -chelator (15), siRNA-based ZEB1 knock-down (10), and CRISPR/Cas9-mediated ZEB1 gene ablation (16,17) methods, none of which can fully elucidate the Zn 2+ -mediated ZEB1 functions. In the present study, to fully address this subject, we produced a mutant ZEB1 expression construct (MutZEB1 (DZn): MutZEB1 for short) that results in a complete loss of the Zn 2+ -binding capacity of ZEB1 by using a novel approach, i.e., replacing all key amino acids that are essential to capture Zn 2+ in all the Zn-finger motifs.…”

Zinc’s Association with the CmPn/CmP Signaling Network in Breast Cancer Tumorigenesis

“…As a result, TNBC is considered a non-responsive breast cancer due to lack of sex steroid hormone-receptor expression and this property of TNBCs is largely responsible for the disease’s aggressive nature, high metastatic potential and worse prognosis, as well as the limited therapeutic options [ 11 , 12 ]. Various properties that contribute to efficacious metastasis include cell motility, invasion, plasticity, and microenvironmental modulation [ 13 ].…”

“…Zinc, one of the essential micronutrients, is involved in a variety of cellular processes such as structural or catalytic components in an assortment of proteins and has been noted to be involved in these metastatic processes as well [ 13 , 14 ]. Zinc is required for the action of more than 300 metalloenzymes, 3000 transcription factors, and thousands of other cellular proteins, which play crucial roles in physiological processes, including antioxidant, anti-inflammatory and immune responses, as well as apoptosis [ 14 , 15 ].…”

“…As zinc supplementation has gradually been applied in nutritional support therapy for cancer patients, further exploration of the regulation of enzyme activity by zinc deficiency in cancer may provide comprehensive guidance for the application of zinc therapy [ 19 ]. Previous studies demonstrated that zinc concentration is especially important in the microenvironment modulation of tumor cells’ acquisition of tumorigenic potential [ 13 ]. Additionally, there is evidence that zinc dyshomeostasis caused by a dysfunctional zinc transporter can contribute to the initiation of various cancers such as prostate, breast, and pancreatic cancers [ 20 ].…”

The importance of targeting signalling mechanisms of the SLC39A family of zinc transporters to inhibit endocrine resistant breast cancer

“…Similarly, high ZIP4 expression correlated with a poorer prognosis for patients. Interestingly, previous work has demonstrated that dysregulation of zinc homeostasis as a result of increased ZIP4 activity, can promote the formation of brain metastasis from triple-negative breast cancer cells [ 28 ]. This study also found that this increased cellular zinc can increase tumourgenic capacity of breast cancer stem cells.…”