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

This proposal constitutes the German part of a joint research project within the DFG- Czech Science Foundation (GACR) cooperation program. It will be performed in collaboration with Prof. Vojtech Adam, head of 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 post-translational 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 aims 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 will investigate the levels and intracellular distribution of free and total zinc, as well as the different MT species. Based on these data, we will examine 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. We will further elucidate potential reciprocal interactions between commonly used cytostatics (cisplatin, doxorubicin, etoposide) and the zinc/MT system. This includes the impact of cytostatics on zinc levels, MT, and zinc-dependent signaling, as well as the impact of zinc/MT status on cytostatic effects on growth, cell cycle distribution, and viability of BCa cells. In the final part we will visualize the zinc distribution in tissue/tumor sections in a murine model (animal experiments will be performed by the partner group in Brno) to compare the in vitro findings to cells grown in an in vivo environment. Together, these results shall identify the importance of zinc/MT within selected BCa subtypes, in order to lay the groundwork for improved prognostic and therapeutic applications. The ultimate aims will be utilizing zinc and MT distribution and speciation for classification of BCa subtypes, and zinc-related signaling as a potential starting point for modulating BCa cell growth and survival.

• DFG Programme: Research Grants
• International Connection: Czech Republic
• Cooperation Partner: Professor Dr. Vojtech Adam