Chronoradiobiology of Breast Cancer: The Time Is Now to Link Circadian Rhythm and Radiation Biology

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.

Melatonin Regulates the Daily Levels of Plasma Amino Acids, Acylcarnitines, Biogenic Amines, Sphingomyelins, and Hexoses in a Xenograft Model of Triple Negative Breast Cancer

“…As a result, during the dark phase melatonin triggers cellular and molecular mechanisms that are expressed only after cessation of the melatonin signal during the following day. Recent studies have reported that biorhythm disorders are closely associated with BC incidence and progression [ 69 ]. For example, the circadian gene TIMELESS was found to be highly expressed in BC conditions, predicting a poor prognosis (e.g., tumor growth) after positive regulation of sphingolipid metabolism [ 34 ].…”

Interval From Simulation Imaging to Treatment Delivery in SABR of Lung Lesions: How Long is Too Long for the Lung?

“…To determine the best cutoff value for DPT based on LC, we used the Youden method. Means between the 2 groups thus defined were compared with a Student t test and proportions with a χ 2 test. To normalize their distribution, some variables were log-transformed.…”

“…Time plays a crucial role in radiation oncology (RO), sometimes in unexpected ways (FLASH–radiation therapy [RT], 1 chrono-RT 2 ). In the treatment of cancer, by definition a progressive disease, avoidance of delays is essential.…”

The effect of chronoradiotherapy on cervical cancer patients: A multicenter randomized controlled study

“…The cell cycle, proliferation, and cell death are closely intertwined with the circadian rhythm. Several recent studies have provided compelling evidence on the association between the circadian cycle and cancer; similar to healthy cells, tumor cells are rhythmic ( 9 , 10 ), and their growth depends on circadian rhythms ( 11 ). It has been reported that each phase of the cell cycle corresponds to a different degree of radiosensitivity ( 12 ).…”