Beating breast cancer: understanding how tissue stiffness affects cancer rates

People with a high mammographic density (HMD) are more likely to develop breast cancer. Dr Isobel Taylor-Hearn is investigating why.

Breast cancer is the leading cause of death in UK women aged between 35 and 49. Routine breast screening doesn’t start until women are 50. Overall, around 12% of the female population will get breast cancer at some point during their lifetime. Despite decades of research and breakthroughs, we still don’t fully understand what triggers the earliest stages of breast cancer. Figuring out these early changes is critical, as it could lead to novel ways of preventing the disease entirely.

Breast cancer risk factors

There are lots of risk factors for breast cancer, including being female, having a family history of the disease, and having certain genetic mutations. But the biggest risk factor, after age, is having high mammographic density (HMD). Simply put, HMD means that there’s a higher amount of dense, opaque tissue visible on a mammogram. People with HMD are more likely to develop breast cancer, but we don’t know why. However, we do know that people with HMD have breast tissue that is stiffer than people with low mammographic density (LMD). Our research therefore focuses on uncovering the link between tissue stiffness and breast cancer initiation.

Studying cells in 3D

Cells behave very differently depending on the stiffness of their surroundings, changing factors including their shape, movement, growth rate, gene expression, and how they attach to each other. However, many studies focusing on how cells respond to stiffness have been done with isolated cells grown on flat surfaces, which is very unlike the organised tissues in the body.

To get a more realistic view, we grow breast cells in 3-dimensional (3D) cultures, where they form tiny hollow spheres, or "acini", that mimic the shape and structure of real breast tissue. In these conditions, breast cells can even make milk. The acini are covered in a thin, protective sheet of protein called a basement membrane, which is important in directing their behaviour. Studying the cells in 3D cultures allows us to see how cells organise, communicate, and function together, and understand how disruption in cellular processes might lead to cancer.

Since breast cancers usually begin in mature adult breast tissue, we focus on studying the effect of microenvironmental stiffness in mature acini. By first growing acini to maturity and then moving them to either a soft or stiff microenvironment, we can investigate how stiffness affects the mature, organised acini.

My research focus

In my research, I’m examining the mechanical forces that breast acini experience when they’re placed in 3D environments of various stiffness levels, mimicking what we see in low and high mammographic density breasts.

I’ve spent many hours on the microscope and developing computational methods to quantify how the cells respond to changes in stiffness, which might give us new clues into how increased stiffness could contribute to breast cancer development.

When mature acini are placed into a soft gel, with a stiffness comparable to LMD breast tissue, the acini remain round, and organised, and don’t grow out of control. However, when breast acini are moved to a stiff gel, they are unable to organise and lose control of their growth. One of the most striking changes in the stiff conditions was the loss of organisation of the basement membrane, the protective layer surrounding the acini. The basement membrane plays a crucial role in providing biochemical and mechanical cues to the cells, and cancerous tissues often have damaged or absent basement membranes, which enables invasion of tumour cells. We have been investigating the initial alterations in basement membrane localisation that could represent an initial step towards malignancy.

Even within the first seven days of transfer, we were able to measure lots of stiffness-dependent changes. Acini in the stiff gel grew larger and contained more cells, though individual cells remained the same size in both gels. We initially thought that cells in the stiff gel might be dividing faster, but it turned out that they weren’t dividing any more quickly; instead, fewer cells were dying, leading to a buildup.

Encouragingly, we found that moving acini from a stiff gel back to a soft gel can restore some of the basement membrane’s organisation. Our latest work has been focused on understanding what causes the breakdown in the first place and exploring if certain drugs can prevent it.

Our findings have revealed that a combination of physical forces and cellular signalling play crucial roles in triggering the changes we observe in stiff environments. Understanding this complex interaction could provide valuable insights into breast cancer initiation and help us to identify new markers for early diagnosis and potential therapeutic strategies to prevent or even reverse these changes.

Words and pictures - Dr Isobel Taylor-Hearn

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