Mast cell tryptase induces nuclear remodelling and reduced growth in breast cancer cells

TL;DR

This study shows that mast cell tryptase can reduce breast cancer cell growth by altering chromatin structure and histone modifications.

Contribution

The study reveals a novel mechanism by which mast cell tryptase regulates breast cancer growth through nuclear entry and chromatin remodeling.

Findings

Tryptase is taken up by breast cancer cells and enters their nuclei, altering chromatin organization.

Tryptase induces truncation of core histone-3 (H3) and reduces associated epigenetic marks.

Tryptase-positive mast cells are associated with reduced tumor cell proliferation in breast cancer models.

Abstract

Mast cells accumulate in breast cancer, but there is only limited knowledge of how they impact on breast cancer growth. Here we show that tryptase, a major compound stored in mast cell secretory granules, has profound effects on breast cancer cell morphology and growth, 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 tumours and in human triple negative breast cancer, and a proliferation clearance zone was seen in the vicinity of tryptase-positive mast cells. It was also observed that mast cells were activated to a higher extent in breast cancer tumours than in healthy tissue. Finally, ATAC-seq analysis revealed that tryptase affected chromatin accessibility at 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.

Figures