Human biology is deeply integrated with the rotation of the Earth: healthy physiology is synchronized with circadian cycles, while unhealthy states are often marked by poor circadian coordination. In certain cancers including breast cancer, striking circadian rhythm dysregulation extends to endocrine, immune, metabolic, and cellular function. Disruption resulting from biological and behavioral influences has been linked with higher incidence and faster tumor progression in humans and animals. The hypothalamic SCN coordinates circadian events at the tissue and cellular level, partly via glucocorticoids that regulate genes involved in tumor growth, cell proliferation, apoptosis, immune cell trafficking, and cytotoxicity. We present a revision of our previously published model of circadian effects in cancer (Sephton and Spiegel, 2003) based on evaluation of new data from divergent lines of investigation. Human clinical studies show circadian endocrine disruption may be accompanied by suppressed functional cellular immunity and overactive inflammatory responses that could promote tumor growth, angiogenesis, and metastasis. Animal data provide strong evidence of clock gene regulation of tumor cell growth. Tissue culture research demonstrates that biologically or behaviorally mediated down-regulation of clock gene expression can accelerate tumor growth. An integrated view suggests mechanisms by which circadian effects on tumor growth may be mediated. These include psychoneuroendocrine and psychoneuroimmune pathways, the relevance of which we highlight in the context of breast cancer. Taken together, data from clinical, systemic, cellular, and molecular research suggest the circadian clock is a tumor suppressor under both biological and behavioral control.
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