Zinc signaling and metallothioneins sub/isoform expression in breast cancer: Implications for prognostic and therapeutic purposes

• Applicant: Professor Dr. Hajo Haase
• Subject Area: Gynaecology and Obstetrics ; Cell Biology
• Term: from 2019 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 412300838

• Final Report Year: 2023

Final Report Abstract

This proposal constitutes the German part of a joint research project within the DFG- Czech Science Foundation (GACR) cooperation program. It was performed in collaboration with Prof. Vojtech Adam, head of the Department of Chemistry and Biochemistry at Brno University of Technology, Czech Republic. Our two groups have longstanding experience investigating the biological roles of zinc and its main intracellular binding protein, metallothionein (MT). Zinc binding by MT is controlled by expression of different isoforms of the protein, and posttranslational modifications including oxidation of metal-binding cysteine thiols and polymerization. The essential trace element zinc is a constituent of over 300 enzymes and an even higher number of other proteins, such as transcription factors. Moreover, free zinc acts as a second messenger, controlling activation, proliferation, and survival of mammalian cells. The zinc/MT system may therefore have a crucial role in cancer cell growth. The present project aimed to elucidate the role of zinc and MT in different forms of breast cancer (BCa), using cell lines representing different breast cancer subtypes as in vitro models. We investigated the levels and intracellular distribution of free and total zinc, as well as the different MT species. Subsequently, we examined the role of zinc-dependent signal transduction for the proliferation and survival of BCa cells, in particular in response to stimulation of receptors relevant for BCa, namely receptors for Epidermal Growth Factor, Progesterone, and Estrogen. In this context, in particular a regulation of Akt-phosphorylation of serine 479 was identified as a target for cellular zinc in mammary cells. We further elucidated potential reciprocal interactions between commonly used cytostatic agents (cisplatin, doxorubicin, etoposide, tamoxifen) and the zinc/MT system, observing a particular effect with tamoxifen that, in contrast to the other chemotherapeutics, was affected by the cellular zinc status. Taken together, our results show an interaction between zinc/MT and the viability of BCa-cells on multiple levels with potential future implications for chemotherapy.

Publications

• „Interaction between zinc and metallothionein in breast cancer” PhD Student Symposium 2019, Berlin
  C. Hübner & H. Haase
  
• Effects of extracellular zinc chelation and supplementation on human breast cancer cell lines” 49. Lebensmittelchemikertag 2021, Hamburg
  C. Hübner, C. Keil, A. Jürgensen, T. Neubert, M. Maares & H. Haase
  
• Interactions of zinc- and redox-signaling pathways. Redox Biology, 41, 101916.
  Hübner, Christopher & Haase, Hajo
  
• Zink in Brustkrebs: Biomarker, second messenger und therapeutisches Target?. Lebensmittelchemie, 75(S1).
  Hübner, C.; Keil, C. & Haase, H.
  
• “Effects of extracellular zinc chelation and supplementation on human breast cancer cell lines” International Conference of Trace Elements and Minerals 2022 (ICTEM), Aachen
  C. Hübner, C. Keil, A. Jürgensen, T. Neubert, M. Maares & H. Haase
  
• Comparison of Three Low-Molecular-Weight Fluorescent Probes for Measuring Free Zinc Levels in Cultured Mammary Cells. Nutrients, 15(8), 1873.
  Hübner, Christopher; Keil, Claudia; Jürgensen, Anton; Barthel, Lars & Haase, Hajo