# Matrix stiffness-induced IKBKE and MAPK8 signaling drives a phenotypic switch from DCIS to invasive breast cancer

## TL;DR

This study identifies how matrix stiffness triggers a shift from non-invasive to invasive breast cancer through specific signaling pathways, suggesting new treatment approaches.

## Contribution

The novel finding is that matrix stiffness activates IKBKE and MAPK8 signaling, driving the transition from DCIS to invasive breast cancer.

## Key findings

- Matrix stiffness activates 53 kinases, with 16 regulated by integrin β1.
- IKBKE and MAPK8 signaling are critical for the stiffness-driven invasive breast cancer phenotype.
- Inhibitors of IKBKE and MAPK8 can revert the invasive phenotype to a non-invasive state.

## Abstract

Ductal carcinoma in situ (DCIS) is not life threatening unless it transitions into invasive breast cancer (IBC). However, although breast cancer cell exposure to matrix stiffening in vitro phenotypically mimics the DCIS to IBC switch, the molecular changes driving this switch remains unclear. Here, breast cancer cell kinome activity profiling suggested matrix stiffness-upregulation of 53 kinases, among which 16 kinases were also regulated by integrin β1. Functional validation identified matrix stiffness-activation of inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKBKE) and mitogen-activated protein kinase 8 (MAPK8) signaling as critical for the stiffness-driven IBC phenotype, including for cell proliferation. The IKBKE-inhibitor Amlexanox, clinically utilized for aphthous ulcers, as well as the MAPK8 inhibitor JNK-IN-8, reinstalled the DCIS-like phenotype of breast cancer cells on high matrix stiffness. This suggests that IKBKE and/or MAPK8 inhibitors could enhance the arsenal of treatments to prevent or treat breast cancer.

The online version contains supplementary material available at 10.1186/s12964-025-02276-y.