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

Marina Vogel-González,Dunia Musa-Afaneh,Pilar Rivera Gil,Rubén Vicente

doi:10.3390/ijms22179188

Marina Vogel-González, Dunia Musa-Afaneh + Show 2 more

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https://doi.org/10.3390/ijms22179188

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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.

Highlights

Triple-negative breast cancer (TNBC) accounts for almost 20% of breast cancers and tends to be more aggressive than non-TNBCs
In order to delineate the relevance of intracellular zinc in TNBC brain metastasis, first we compared the zinc concentration in the basal condition between MDA-MB-231 and BrM2 cells, our TNBC model for brain metastasis
Using Zinquin as a zinc content reporter, we observed that BrM2 cells had double the zinc content of MDA-MB-231 cells (Figure 1A)

Summary

Introduction

Triple-negative breast cancer (TNBC) accounts for almost 20% of breast cancers and tends to be more aggressive than non-TNBCs. Given that TNBC lacks expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), it cannot be targeted by specific treatments. For this reason, TNBC tumors have a higher rate of distant recurrence [2]. After acquiring all of the characteristics needed to be tumorous, present the so-called hallmarks of metastasis: motility and invasion, microenvironment modulation, plasticity, and colonization [5]. To achieve colonization of the secondary niche, the tumor has to proliferate in situ, thanks to the interaction between the microenvironment and cells derived from these CSCs [5]

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