Mechanotransduction tuned by intermediate filaments promotes DNA repair in stiff environments

High mammographic density increases breast cancer risk. Dense tissues are rich in fibrillar collagen, forming a rigid extracellular matrix around the epithelium. Although cancer initiation and progression are closely tied to DNA damage and to the DNA damage response, if and how tissue stiffness affects genome maintenance is not fully elucidated. We found that repair factor recruitment is more efficient, and that DNA breaks are repaired faster by cells on rigid substrates. Mechanistically, hemidesmosomal integrins, intermediate filaments, the LINC complex, and YAP are key mediators of this mechanogenomic response. Rigid tissue contexts favor survival of cells with DNA damage, which may lead to the accumulation of somatic mutations, as identified here with RNAseq analyses of normal breast tissue. Our findings provide new insights into how tissue rigidity influences cancer risk.