Circadian clocks and breast cancer - PubMed (original) (raw)

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Circadian clocks and breast cancer

Victoria Blakeman et al. Breast Cancer Res. 2016.

Abstract

Circadian clocks respond to environmental time cues to coordinate 24-hour oscillations in almost every tissue of the body. In the breast, circadian clocks regulate the rhythmic expression of numerous genes. Disrupted expression of circadian genes can alter breast biology and may promote cancer. Here we overview circadian mechanisms, and the connection between the molecular clock and breast biology. We describe how disruption of circadian genes contributes to cancer via multiple mechanisms, and link this to increased tumour risk in women who work irregular shift patterns. Understanding the influence of circadian rhythms on breast cancer could lead to more efficacious therapies, reformed public health policy and improved patient outcome.

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Figures

Fig. 1

Fig. 1

The core molecular circadian clock mechanism. Twenty-four-hour cellular rhythms are driven by an autoregulatory feedback loop. During the subjective day, RORα contributes to expression of Bmal1 through its retinoic acid-related orphan receptor response element (RRE). The resulting CLOCK/BMAL1 complex activates transcription of the negative regulators, Per and Cry. By the evening PER and CRY levels accumulate to form a protein complex, which then becomes active as a CLOCK/BMAL1 inhibitor. During the subjective night, REV-ERBα suppresses expression of Bmal1, while the newly formed PER/CRY complex blocks CLOCK/BMAL1 activity, thereby preventing further transcription from the Per and Cry genes. During this time, the phosphorylated PER/CRY complex gradually degrades

Fig. 2

Fig. 2

Circadian disruption can drive breast cancer. a Intrinsic factors such as genetic defects or ageing, and extrinsic factors such as irregular shift work, can severely disrupt the body’s internal timing system. b In turn these factors, either singularly or collectively, link a faulty circadian clock to an increased risk of breast cancer. A faulty clock can directly disrupt the gating of the cell cycle and reduce apoptosis, These effects can also be brought on indirectly through altered metabolism in response to a broken circadian clock. They can also lead to elevated EMT, driving the formation of lethal metastases. A further mechanism that can link to breast cancer is arrhythmic production of melatonin, tipping the balance towards tumorigenesis. EMT epithelial–mesenchymal transition

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