Matrix stiffness drives alterations in aldehyde metabolism, inducing DNA damage and transformation.

Microenvironmental stiffness regulates fundamental aspects of cell behaviour, including proliferation, differentiation and metabolism, many of which are implicated in cancer initiation and progression. In the mammary gland, extracellular matrix (ECM) stiffness, associated with high mammographic density, is linked to increased breast cancer incidence. However, a mechanistic link between increased ECM stiffness and the genomic damage required for transforming mutations remains unclear. Here we show that ECM stiffness induces changes in mammary epithelial cell (MEC) metabolism which drive DNA damage. Using a mechanically tunable 3D-culture model, we demonstrate that transcriptional changes in response to increased ECM stiffness impair the ability of MECs to remove reactive aldehydes. Downregulation of multiple aldehyde dehydrogenase isoforms in MECs within a stiffer 3D ECM leads to higher levels of reactive aldehydes, resulting in genomic damage and transformation. Together, these results provide a mechanistic link between increased ECM stiffness and the genomic damage required for breast cancer initiation.