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Review
. 2011 Oct;51(3):259-69.
doi: 10.1111/j.1600-079X.2011.00888.x. Epub 2011 May 24.

Circadian Regulation of Molecular, Dietary, and Metabolic Signaling Mechanisms of Human Breast Cancer Growth by the Nocturnal Melatonin Signal and the Consequences of Its Disruption by Light at Night

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Free PMC article
Review

Circadian Regulation of Molecular, Dietary, and Metabolic Signaling Mechanisms of Human Breast Cancer Growth by the Nocturnal Melatonin Signal and the Consequences of Its Disruption by Light at Night

David E Blask et al. J Pineal Res. .
Free PMC article

Abstract

This review article discusses recent work on the melatonin-mediated circadian regulation and integration of molecular, dietary, and metabolic signaling mechanisms involved in human breast cancer growth and the consequences of circadian disruption by exposure to light at night (LAN). The antiproliferative effects of the circadian melatonin signal are mediated through a major mechanism involving the activation of MT(1) melatonin receptors expressed in human breast cancer cell lines and xenografts. In estrogen receptor (ERα+) human breast cancer cells, melatonin suppresses both ERα mRNA expression and estrogen-induced transcriptional activity of the ERα via MT(1) -induced activation of G(αi2) signaling and reduction of 3',5'-cyclic adenosine monophosphate (cAMP) levels. Melatonin also regulates the transactivation of additional members of the steroid hormone/nuclear receptor super-family, enzymes involved in estrogen metabolism, expression/activation of telomerase, and the expression of core clock and clock-related genes. The anti-invasive/anti-metastatic actions of melatonin involve the blockade of p38 phosphorylation and the expression of matrix metalloproteinases. Melatonin also inhibits the growth of human breast cancer xenografts via another critical pathway involving MT(1) -mediated suppression of cAMP leading to blockade of linoleic acid uptake and its metabolism to the mitogenic signaling molecule 13-hydroxyoctadecadienoic acid (13-HODE). Down-regulation of 13-HODE reduces the activation of growth factor pathways supporting cell proliferation and survival. Experimental evidence in rats and humans indicating that LAN-induced circadian disruption of the nocturnal melatonin signal activates human breast cancer growth, metabolism, and signaling provides the strongest mechanistic support, thus far, for population and ecological studies demonstrating elevated breast cancer risk in night shift workers and other individuals increasingly exposed to LAN.

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Figure 1
Figure 1
Impact of the nocturnal circadian melatonin signal, via the MT1 receptor, and its disruption by LAN on molecular/endocrine and dietary/metabolic regulatory mechanisms governing breast cancer initiation, growth promotion and progression. Abbreviations used are: 13-HODE (13-hydroxyoctadecadienoic acid), 17βHSD (17β-hydroxysteroid dehydrogenase), Akt (Serine/Threonine Protein Kinase), Bax (Bcl-2-Associated × Protein), BMAL1 (Brain and Muscle Aryl Hydrocarbon Receptor Nuclear Translocator – Like 1), BRCA 1 & 2 (Breast Cancer 1 & 2), CLOCK (Circadian Locomotor Output Cycles Kaput), EGFR (Epidermal Growth Factor Receptor), ERα (Estrogen Receptor Alpha), Erk (Extracellular Signal-Regulated Kinase), ERRα (Estrogen Related Receptor Alpha), EST (Estrogen Sulfotransferase), IGF-1R (Insulin-like Growth Factor-1 Receptor), MMP (Matrix Metalloproteinase), MT1 (Melatonin Receptor 1), Per 1, 2 (Period 1, 2), PGC1α (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha), PPARγ (Peroxisome Proliferator-Activated Receptor Protein Gamma), RARα (Retinoic Acid Receptor Alpha), Rev-erbα (aka NR1D1, Nuclear Receptor Subfamily 1, group D, member 1), RORα (RAR-related Orphan Receptor Alpha), R×Rα (Retinoid × Receptor Alpha), SIRT1 [Sirtuin (Silent Mating Type Regulation 2 Homolog) 1], STS (Estrogen Sulfatase). Figure adapted and modified from reference [19].

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