Circadian clocks are fundamental, time-tracking systems that allow organisms to adapt to the time of day, and drive many cellular processes, including proliferation and metabolism. Epidemiological evidence has shown that alteration of circadian rhythms via night-shift work, chronic jet lag, or other conditioning, leads to increased susceptibility to breast and other cancers, worse patient prognoses, and drug resistance during cancer treatment. While critical elements of this system have been linked to cancer or its suppression, and mistimed and insufficient sleep have been shown to disrupt circadian regulation of protein expression, there have been no studies directly examining the effect of circadian rhythm perturbation on cancer at a molecular level. In our work, we have generate luminescent cellular reporters for proteins that are part of the core clock and cancer associated proteins that are under clock control. We have incorporated these constructs into breast cancer cell lines representing different breast cancer subtypes and stages of progression, and are able to assess circadian oscillations in a high-resolution manner using real time luminometry. We are using these models in combination with small molecule modulators of the circadian rhythm in order to correlate changes in oscillations with oncogenic effects. In these systems, we have used small molecules to affect circadian rhythms via period-lengthening, -shortening, phase delay induction, and amplitude enhancement. We show that by altering the circadian rhythms, we can also affect the properties of cells, including their proliferation and motility. In the future, we aim to use small molecules to re-normalize circadian rhythms as potential treatments for cancer and other diseases.<br/><br/>We hypothesize that increasing deviations in circadian rhythm will correlate with higher aggression and metastatic potential in cancer, and that by altering abnormal rhythms we can ameliorate aggressive and metastatic cancers. These studies will enable us to use the knowledge gained in connecting circadian rhythm to cancer, and convert it into new classes of therapeutics for treatment of the disease.<br/>

Chemical modulation of circadian rhythms in models of breast cancer

256th National Meeting (2018)

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