Understanding how targeting zinc transporters prevents the development of aggressive cancer

Zinc is one of the most abundant trace elements in the human body. Cellular zinc homeostasis is primarily controlled by zinc transporters, including the ZIP family of zinc importers. Since zinc homeostasis needs to be tightly controlled, dysregulation of these zinc transporters is associated with multiple diseases including cancer. ZIP7, a zinc transporter residing on the endoplasmic reticulum membrane, was discovered to be involved in driving endocrine resistant breast cancer. Findings within this project support the hypothesis that tamoxifen-resistant breast cancer cells are driven by the increased activation of ZIP7 which, together with ZIP6, drives the invasive behaviour of this more aggressive breast cancer phenotype. This study confirmed the suitability of activated ZIP7 as a good biomarker of acquired resistance to anti-hormone treatment in breast cancer, a current clinical unmet need. Zinc is also important in cell cycle progression and, in particular, is essential for progression of cells through the G2 phase and mitosis. Our group have discovered that ZIP6 forms a heteromer with ZIP10 on the plasma membrane which influxes zinc into cells to trigger mitosis. This study demonstrated that treatment of different cancer cell lines with specific N-terminal ZIP6 or ZIP10 antibodies was able to inhibit mitosis by preventing the zinc influx necessary at this stage of the cell cycle. These agents were also shown to be effective at reducing the growth of different cancer cell lines. Using a model of ZIP6 CRISPR/Cas9 knockout cells it was discovered that ZIP6 downregulation induces upregulation of ZIP10, as a compensatory mechanism to counteract the lack of ZIP6. This study revealed novel targets for proliferative diseases such as cancer, which is manifested by uncontrolled growth. Additionally, this project brought new insight into the regulation of ZIP6 and discovered the potential for CK2 phosphorylation as well as proteolytic cleavage for proper function.