To investigate the role of circadian clock in breast cancer
Nan Yang, University of Manchester
The Nobel Prize Award 2017 highlighted an important role of circadian clock in human health and diseases. However, the understanding of circadian regulation of breast development remains limited. Our lab has identified the mammary clock using mouse models (Yang et al., 2017). Strikingly, the clock mutant mice showed compromised stem cell renewal capacity. Also, the mammary clock is regulated by extracellular matrix stiffness. Primary mammary epithelial cells present more robust circadian clock oscillation in soft 3D matrigel culture than 2D petri-dish alone. This finding is consistence with clinical mammographic data observed in patients with breast cancer. The density of breast cancer is always higher than normal breast tissues. To further study the interaction between circadian clock and breast cancer, I would like to focus on how circadian factors regulate the key transcriptional factor - estrogen receptor (ER) in mammary gland. And the overall aims of my study are:
- to identify the expression level of key clock proteins in different types of breast cancer
- to study interaction of clock proteins and ER at genome-wide level
- to investigate the role of clock compounds in breast cancer treatment
This grant supported me to visit Prof Guilak’s lab at Washington University in St Louis, USA. I learnt how the Guilak lab translates circadian biology into different tissue culture models using cutting-edge engineering technologies, such as 3D remodelling. Also, the Guilak lab has developed a method to create different cell patterns to mimic different in vivo environments. Then the system can be used to investigate how tissue stiffness/ mechanobiology determines cell fate. This opportunity to learn new skills, technologies, and to build my network was very helpful for me to establish myself as an independent research scientist in the future.
Difficulties- The grant was originally designed to investigate the role of circadian clock in breast cancer. Unfortunately, my research funding in Manchester was terminated in 2018, and I had to relocate to a different lab. As a result, I wasn’t able to use clock mutant mice, nor breast cancer samples which mentioned in my research proposal.
Went well- I moved to University of Oxford in January 2019. My new research projects are focus on identifying potential therapeutic targets in fibrosis and tissue regeneration. I have been able to integrate my placement experience into my new environment, and I plan to use in vitro analysis of primary human tissue/cells to find new drug targets for fibrotic disease.
At the molecular level, tissue stiffness plays a key role in the development of various diseases, including breast cancer and fibrosis. The Guilak lab was an excellent environment for me to gain new experience, as they have developed new technology to manipulate the extracellular matrix environment in vitro, using modern engineering technologies. I believe that the skills and contacts I have now will enhance my ability to study the role of extracellular matrix in human disease.
Grant awarded: £2,000