The Pathophysiologic Role of Disrupted Circadian and Neuroendocrine Rhythms in Breast Carcinogenesis

Abstract

Most physiological processes in the brain and body exhibit daily (circadian) rhythms coordinated by an endogenous master clock located in the suprachiasmatic nucleus of the hypothalamus that are essential for normal health and functioning. Exposure to sunlight during the day and darkness at night optimally entrains biological rhythms to promote homeostasis and human health. Unfortunately, a major consequence of the modern lifestyle is increased exposure to sun-free environments during the day and artificial lighting at night. Additionally, behavioral disruptions to circadian rhythms (ie, repeated transmeridian flights, night or rotating shift work, or sleep disturbances) have a profound influence on health and have been linked to a number of pathological conditions, including endocrine-dependent cancers. Specifically, night shift work has been identified as a significant risk factor for breast cancer in industrialized countries. Several mechanisms have been proposed by which shift work-induced circadian disruptions promote cancer. In this review, we examine the importance of the brain-body link through which circadian disruptions contribute to endocrine-dependent diseases, including breast carcinogenesis, by negatively impacting neuroendocrine and neuroimmune cells, and we consider preventive measures directed at maximizing circadian health.

Figure 1.

A, Estimated breast cancer incidence worldwide 2012. Rates are age-standardized (per 100 000). GLOBOCAN 2012, International Agency for Research on Cancer, World Health Organization. (From Ref. .) B, World light pollution at night. National Oceanic and Atmospheric Administration (NOAA) National Geophysical Data Center. Data were collected by the U.S. Air Force Weather Agency under the Defense Meteorological Satellite Program, 1994–1995. Data courtesy Marc Imhoff of NASA Goddard Space Flight Center and Christopher Elvidge of National Oceanic Atmospheric Administration, National Geophysical Data Center. Image by Craig Mayhew and Robert Simmon, NASA Goddard Space Flight Center.

Figure 2.

A, Circadian rhythm generation at the cellular level. Circadian rhythms are generated by TTFLs of the core circadian genes. CLOCK and BMAL1 increase the transcription of Period (Per), Cryptochrome (Cry), and other clock-controlled genes during the day. In the classic view, the levels of Per and Cry proteins increase during the night, after which they dimerize and translocate to the nucleus to repress CLOCK–BMAL1-mediated transcription. Per and Cry proteins are then ubiquitylated and degraded to initiate a new circadian cycle. Conversely, REV-ERBα (encoded by Nr1d1) protein levels are high during the day and inhibit BMAL1 transcription at this time. At night, REV-ERBα protein levels are low, allowing BMAL1 transcription to take place. P, Phosphorylation; RRE, REV-ERB/ROR response elements; Ub, ubiquitylation. (From Ref. .) B, Circadian organization at the systems level. A contemporary view of circadian organization in which a hypothalamic pacemaker, in the SCN, communicates through various neural and endocrine links to drive and/or synchronize rhythms in peripheral physiology and behavior. This ensures that as individuals progress through the regular 24-hour cycle of sleep (gray shading) and wakefulness, their metabolism is adjusted accordingly to anticipate the demands and opportunities of the solar day. ANS, Autonomic nervous system. (From Ref. 25).

Figure 3.

The pleiotropic effects of circadian disruption. Circadian disruption affects multiple organ systems. The diagram provides examples of how circadian disruption negatively impacts the brain and the digestive, cardiovascular, and reproductive systems. Although the diagram displays unidirectional effects, there are various feedback loops that exist within the system and interactions that occur between these systems. (From Ref. .)

Figure 4.

Circadian control of cell proliferation and apoptosis at the systemic level. Light and other environmental cues reach the SCN through various input pathways. The SCN clock synchronizes with the environment to generate endogenous rhythms, which are transmitted through output pathways to peripheral tissues. Representative output pathways, such as the autonomic nervous system (ANS) and the hypothalamic-pituitary-gonadal (HPG) and hypothalamic-pituitary adrenal (HPA) axes, are shown. The pineal gland and peripheral tissues can also feed back to SCN or HPA axes through the production of melatonin to regulate homeostasis. Melatonin binds to receptors on SCN neurons to induce phase shifts (202, 205). The adrenal glands produce glucocorticoids, which have negative feedback on the hypothalamus to terminate the release of corticotropin-releasing hormone (CRH) (205). The products of immune activity, such as interferon-α and -γ and interleukin-1, can also modulate the activity of SCN, as well as the HPA axis (206, 207). Feedback pathways are indicated by dashed lines. (From Ref. .)

Figure 5.

Circadian control of cell proliferation and apoptosis at the cellular level. Circadian clock and the cell cycle. The circadian clock is coupled to the cell cycle by clock-controlled genes that have either E-box or RAR-related orphan receptor elements in their promoters. Without detailing post-transcriptional products and downstream pathways, this figure indicates where clock-controlled genes and proteins may potentially interact with the cell cycle. (From Ref. .)