Modelling the impact of increased extracellular matrix stiffness on mammary epithelial cells

Mammographic density (MD) refers to the proportion of the breast occupied by radiographically dense tissue, as assessed by mammography.

It has been shown that women with significantly higher MD are four times more likely to develop breast cancer than those with predominantly radio-lucent tissue.

High MD is associated with increased stiffness of the stromal extracellular matrix (ECM) surrounding the breast epithelial ducts.

Despite a clear mechanistic link between ECM stiffness and breast cancer risk, little is known about how mammary epithelial cells (MECs) sense and respond to the altered mechanical properties of the surrounding microenvironment.

We want to understand how MECs within the duct mechanically sense altered stiffness of their surrounding ECM by using 3D culture models combined with mathematical modelling.

We will utilise 3D traction force microscopy (TFM) to measure the forces on MECs within a 3D ECM model of tuneable mechanical stiffness.

We will use these observations, alongside other biological readouts, to parameterise an individual-cell based mathematical model of a 3D acinar structure.

We will develop this model to provide quantitative predictions enabling mechanistic insight into the behaviour of MECs and the link between high mammographic density and increased breast cancer risk.