Systematic characterization of zinc in a series of breast cancer cell lines reveals significant changes in zinc homeostasis

Abstract

An optimal amount of labile zinc (Zn2+) is essential for proliferation of human cells, where Zn2+ levels that are too high or too low cause cell cycle exit. Tumors of the breast have been characterized by high levels of total Zn2+. Given the role of Zn2+ in proliferation of human cells and elevation of zinc in breast cancer tumors, we examined the concentration of total and labile Zn2+ across a panel of 5 breast cancer cell lines, compared to the normal MCF10A cell line. We found that three cell lines (MDA-MB-231, MDA-MB-157, and SK-Br-3) showed elevated labile Zn2+ in the cytosol, while T-47D showed significantly lower Zn2+, and MCF7 showed no change compared to MCF10A cells. There was no change in total Zn2+ across the cell lines, as measured by ICP-MS, but we did observe a difference in the cells ability to accumulate Zn2+ when Zn2+ in the media was elevated. Therefore, we examined how proliferation of each cell line was affected by increases and decreases in the media. We found striking differences, where three cancer cell lines (MDA-MB-231, MDA-MB-157, and MCF7) showed robust proliferation in high Zn2+ at concentrations that killed MCF10A, T-47D, and SK-Br-3 cells. We also discovered that 4 of the 5 cancer cell lines demonstrate compromised proliferation and increased cell death in low Zn2+, suggesting these cells may be addicted to Zn2+. Overall, our study suggests significant differences in Zn2+ homeostasis and regulation in different types of breast cancer cells, with consequences for both proliferation and cell viability.