Mast cell tryptase induces nuclear remodeling in breast cancer cells and has a negative impact on breast cancer cell growth

Mast cells are known to accumulate in breast cancer, but there is only limited knowledge of how they may impact on breast cancer growth. Tryptase is one of the major compounds stored in the mast cell secretory granules, and here we investigated whether tryptase can have an influence on breast cancer cells. Our findings reveal that tryptase has profound effects on breast cancer cell morphology and that tryptase has a negative impact on the growth of breast cancer cells, the latter by a combination of anti-proliferative and pro-apoptotic effects. Mechanistically, we show that tryptase is taken up by breast cancer cells, and enters their nuclei. Further, tryptase was shown to cause major effects on chromatin organization, and to induce truncation of core histone 3 (H3). H3 truncation was accompanied by reduced levels of epigenetic marks associated with H3. In vivo, tryptase-positive mast cells were found in PyMT breast cancer tumors in mice, and a proliferation clearance zone was seen in the vicinity of tryptase-positive mast cells. Similarly, a proliferation clearance zone was observed in the vicinity of tryptase-positive mast cells in human triple negative breast cancer. It was also observed that mast cells were activated to a higher extent in breast cancer tumors than in healthy breast tissue. In agreement with an anti-proliferative impact of tryptase on breast cancer, ATAC-seq analysis revealed that tryptase affected chromatin accessibility at several regions of the genome associated with genes known to influence breast cancer growth. Altogether, the present study introduces a mechanism for how mast cell tryptase can regulate breast cancer cell growth.