Charles Streuli, MA PhD
Integrins in breast biology

How cell-matrix adhesion controls breast biology

Understanding how epithelia form and function, and the mechanisms leading to their deregulation in disease, are fundamental biological questions of our time. My research focusses on how cells translate the language of their extracellular matrix into the responses that define tissue behaviour. We study the breast because it is an excellent system to uncover basic principles of cell and developmental biology, and because our work can reveal new targets and pathways for treating breast cancer. We’d like to know how the cellular microenvironment controls the way that breast epithelia function and how it influences the rhythmic variations that occur during everyday circadian cycles. We also aim to determine how the matrix impacts on the susceptibility of breast epithelia to becoming cancerous. Importantly, the molecular principles that define how the epithelia of breast tissue function will reveal mechanisms underpinning the biology of all epithelia.

The breast is a three-dimensional organ, which contains an intricate network of epithelial ducts and associated alveoli that are embedded within a stromal connective tissue made up of extracellular matrix. The alveoli are milk factories and the ducts are tubes that transport milk to the nipples. Both require the extracellular matrix to develop properly, and for the breast to work as a secretory organ. Understanding the molecular basis for how the extracellular matrix functions in breast underpins the research in our laboratory.

Sometimes, cells in ducts or alveoli can become cancerous. One of the central problems in cancer is that cell adhesion to the extracellular matrix changes. Either the extracellular matrix stiffens, or the cell’s integrin receptors adjust subtly, or alternatively the intracellular enzymes that integrins control become mutated. The cells then don’t know how to behave properly. For these reasons, we are also determining how cell-matrix interactions are involved with the onset of breast cancer in susceptible patients.

 

Current scientific interests

 

1: Differentiation and breast biology. Over many years we have studied the lactation programme, and have demonstrated a key role for the cellular microenvironment in breast function. Using 3-dimensional culture models, and cells with altered gene expression, as well as gene knockouts in vivo, we discovered that integrin receptors and their downstream signalling molecules, have a central role in the formation of functional lactating tissue. We have a keen interest in how the signals derived from extracellular matrix can alter normal breast cell behaviour to cause cancer, where we are working together with Dr Andrew Gilmore. In collaboration with Dr Ahmet Ucar, we are also studying the integrin-signalling protein Rac1, focussing on its role in both normal and cancerous breast tissue.

 

2: Mammographic density and breast cancer risk. High mammographic density, and the consequent stiff tissue microenvironment provided by the extracellular matrix, is one of the greatest risk factors for breast cancer. However the mechanisms by which ‘stiffness’ contributes to cancer are not understood at all. In collaboration with Dr Mike Sherratt and clinical colleagues, our research is examining how breasts with different mammographic densities are formed. We are also investigating how ‘mechanotransduction’ pathways control the way that epithelial cells behave and how they might trigger breast cancer in post-menopausal women.

 

3: Circadian clocks in the breast. In collaboration with Dr Qing-Jun Meng, we discovered that the breast shows dramatic changes in gene expression over 24-hour ‘circadian’ time periods. We found that mechanical signals from the extracellular matrix control the circadian clock, whereby the stiff microenvironment that becomes more prominent during ageing, suppresses the expression of numerous ‘clock’ genes. Indeed, cell-matrix interactions link to the circadian clock via integrin signalling proteins, such as talin, vinculin, and the cytoskeleton. We have also discovered that clock genes determine the behaviour of breast epithelial stem cells, and are therefore crucial for normal development and function of the tissue.

 

Recent key publications

Yang, N., Williams, J., Pekovic-Vaughan, V., Wang, P., Olabi, S., McConnell, J., Gossan, N., Hughes, A., Cheung, J., Streuli, C.H.* and Meng, Q.-J.* (2017) Cellular mechano-environment regulates the mammary circadian clock. Nat Commun. 8, 14287. PubMed.*Joint senior/contributing authors.

McConnell, J.C., O’Connell, O.V., Brennan, K., Weiping, L., Howe, M., Joseph, L., Knight, D., O’Cualain, R., Lim, Y., Leek, A., Waddington,  R.,  Rogan, J., Astley, S.M., Gandhi, A., Kirwan, C.C., Sherratt, M.J.*  and Streuli, C.H.* (2016) Raised mammographic density is associated with increased peri-ductal collagen micro-organization and micro-stiffness. Breast Cancer Res. 18, 5. PubMed

Akhtar, N., Li, W., Mironov, A. and Streuli, C.H. (2016) Rac1 controls morphogenesis and tissue-specific function in mammary gland development. Dev Cell. 38, 522-535.PubMed     

Full list of publications