Utilising circadian rhythms to optimise therapies for breast cancer

Breast cancer represents the most common cancer among women. Current therapies, including the extended use of endocrine therapies, the adjuvant chemotherapeutic regimens, and the targeted drugs for HER2+ cancers, have greatly improved outcomes of women with breast cancer. However, despite the application of such therapies, resistance and subsequent relapse are major issues. Therefore, there is a constant need to improve the therapeutic index for better efficacy and lower adverse effects. Animal and epidemiological studies have proposed that night shift work which disrupts circadian rhythms increase risks of developing breast and other cancers (Van Dycke et al Curr Biol 2015; Cordina-Duverger et al Eur J Epidemiology 2018; Ward et al Lancet Oncol 2019). However, up till now, the underlying mechanisms remain largely unknown. The cell intrinsic circadian clocks are critical regulators of metabolism, differentiation, DNA damage response and cell cycle. Our preliminary data show that circadian clock function is retained in certain breast cancers but lost in other subtypes. However, unresolved questions are how the intrinsic molecular clocks are regulated in primary breast cancers and whether timing of therapy based on clock cycle may lead to improved outcomes.

In this PhD project, we will utilize RNA deep sequencing, machine learning algorithms, real-time imaging of clock gene activities, and in vitro, ex vivo and in vivo models of breast cancer to 1) investigate how hormones and HER2 signalling are involved in regulating breast cancer clocks, 2) uncover rhythmic genes, pathways and their functions in breast tumours; 3) test a "circadian medicine" approach in breast cancer cells and in mouse models carrying patient derived xenografts in vivo. This project will provide fresh new insights into the functions of cell intrinsic molecular clocks in breast cancer cells, and directly evaluate the possibility of utilising clock timing to guide therapies.