Abstract
Circadian disruption has been linked to cancer development, progression, and radiation response. Clinical evidence to date shows that circadian genetic variation and time of treatment affect radiation response and toxicity for women with breast cancer. At the molecular level, there is interplay between circadian clock regulators such as PER1, which mediates ATM and p53-mediated cell cycle gating and apoptosis. These molecular alterations may govern aggressive cancer phenotypes, outcomes, and radiation response. Exploiting the various circadian clock mechanisms may enhance the therapeutic index of radiation by decreasing toxicity, increasing disease control, and improving outcomes. We will review the body’s natural circadian rhythms and clock gene-regulation while exploring preclinical and clinical evidence that implicates chronobiological disruptions in the etiology of breast cancer. We will discuss radiobiological principles and the circadian regulation of DNA damage responses. Lastly, we will present potential rational therapeutic approaches that target circadian pathways to improve outcomes in breast cancer. Understanding the implications of optimal timing in cancer treatment and exploring ways to entrain circadian biology with light, diet, and chronobiological agents like melatonin may provide an avenue for enhancing the therapeutic index of radiotherapy.
Highlights
We explore the fundamentals of chronobiology, focusing on the relationship to breast cancer pathogenesis, treatments, toxicity, and outcomes
We propose practical methods for leveraging circadian rhythms that may someday be used in radiotherapy, with potential roles for time-restricted diets and chronopharmaceuticals
Circadian disruption is associated with an increased breast cancer risk in women. (RR = 1.14; 95% CI 1.08–1.21)
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Decades of research demonstrate that radiation responses vary across an organism’s circadian period. The emerging field of chronoradiobiology examines the biological relationships between the complex mechanisms of circadian regulation and cellular radiation responses with the goal of improving the therapeutic index of radiation treatments. Understanding circadian regulation, disruptions, and downstream effects that can impact radiation therapy could lead to potential improvements for patients. Data on circadian disruption and clock gene regulation may lead to new approaches to personalize care. We explore the fundamentals of chronobiology, focusing on the relationship to breast cancer pathogenesis, treatments, toxicity, and outcomes. The epidemiological and molecular associations of breast cancer with circadian pathways will be discussed as well as the interplay of circadian clock genes and radiation therapy. We propose practical methods for leveraging circadian rhythms that may someday be used in radiotherapy, with potential roles for time-restricted diets and chronopharmaceuticals
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